Aminopyridine compounds

ABSTRACT

An aminopyridine compound represented by the formula: ##STR1## wherein n represents 0 or 1; Z represents ═S, ═O, ═NCN or ═CHNO 2  ; R 1  represents --CN, --NR 3  R 4 , --CONR 3  R 4 , --NHNR 3  R 4 , --NHCONHR 3 , --NHSO 2  R 3  or --SR 3  ; R 2  represents H, or substituted or unsubstituted alkyl; R 3  and R 4 , which may be the same or different, represent H, substituted or unsubstituted alkyl, aryl, substituted or unsubstituted acyl or alkoxycarbonyl group; and R 3  and R 4  may form a heterocyclic ring together with a nitrogen atom to which R 3  and R 4  are bound, through another heteroatom or without it; or an acid salt thereof, which is excellent in pharmacological effect and repressed in side effects as a drug for circulatory diseases.

FIELD OF THE INVENTION

The present invention relates to novel aminopyridine compounds useful asagents for treating diseases of the circulatory system.

BACKGROUND OF THE INVENTION

As agents for the circulatory system, particularly therapeutic agentsfor hypertension, various compounds are commercially available orcurrently under development. In recent years, the possibility oftreatment of circulatory diseases based on a new mechanism called"potassium channel opener" has been suggested and various investigationshave been made, based on this theory.

Typical examples of drugs based on the above mechanism are Pinacidil[N"-cyano-N-4-pyridyl-N'-(1,2,2-trimethylpropyl)guanidine] having anN-pyridyl-N'-cyanoguanidine skeleton and Cromakalim[(+,-)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H -benzo(b)pyran-3-ol]having a benzopyran skeleton.

At present, however, it cannot be said that Pinacidil nor Cromakalimpossess sufficient pharmacological effects without side effects. Inparticular, Pinacidil causes stagnation as a side effect, and theproblems of edema, vascular headache, cardiopalmus, etc. remainunsolved.

In order to solve the above problems, new compounds thought to have animproved overall pharmacological effect are currently underinvestigation.

As such compounds, N-alkyl-N'-pyridyl-thioureas andN-alkyl-N'-pyridyl-N'-cyanoguanidines [JP-A-51-86474 (the term "JP-A" asused herein means an "unexamined published Japanese patent application")and JP-A-52-83573 corresponding to U.S. Pat. No. 4,057,636] andN-substituted-N-aryl-thioureas andN-substituted-N-aryl-N'-cyanoguanidines (JP-A-2-91057 corresponding toEP 354553 and JP-A-2-290841 corresponding to EP 392802) have beenreported.

SUMMARY OF THE INVENTION

The present inventors conducted intensive investigation in view of theabove-described situation. As a result, the present inventors succeededin synthesizing novel compounds showing excellent pharmacological effectand relieved side effects, compared to Pinacidil which is a knowncompound, and other compounds having similar structures.

The present invention provides aminopyridine compounds represented byformula (1): ##STR2## wherein n represents 0 or 1; Z represents ═S, ═O,═NCN or ═CHNO₂ ; R₁ represents --CN, --NR₃ R₄, --CONR₃ R₄, --NHNR₃ R₄,--NHCONHR₃, --NHSO₂ R₃ or --SR₃ ; R₂ represents H or substituted orunsubstituted alkyl; R₃ and R₄, which may be the same or different,represent H, substituted or unsubstituted alkyl, aryl, substituted orunsubstituted acyl or alkoxycarbonyl group; and R₃ and R₄ may form aheterocyclic ring together with the nitrogen atom to which R₃ and R₄ arebound, which ring may include another heteroatom and/or containunsaturation; and the pharmaceutically acceptable acid salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the alkyl group is preferably a lower alkylgroup having 1 to 10 carbon atoms. The alkyl group may be straight orbranched chain having 1 to 7 carbon atoms. Specific examples thereofinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, n-pentyl, n-hexyl, 1,2,2-trimethylpropyl, 2-methylpropyl and1,1-dimethylpropyl. This type alkyl group may have a substituent groupsuch as a hydroxyl group or an amino group. R₂ is preferably a branchedalkyl such as 1,2,2-trimethylpropyl, 2-methylpropyl and1,1-dimethylpropyl.

The alkyl group can be a cycloalkyl group. The cycloalkyl groups includemonocycloalkyl, bicycloalkyl, tricycloalkyl and polycycloalkyl groups.Preferably, the cycloalkyl group has 5 to 10 carbon atoms. Specificexamples thereof include cyclopentyl, cyclohexyl and cycloheptyl.Examples of the bicycloalkyl groups include norbornyl, pinanyl andbicyclo-[2,2,2]-octyl, and examples of the tricycloalkyl andpolycycloalkyl groups include adamantyl. The cycloalkyl group may have asubstituent group such as an alkyl group. R₂ is preferably bicycloalkylshaving 7 to 10 carbon atoms such as bicyclohexyl, norbornyl, pinanyl,bicyclo-[2,2,2]-octyl.

Examples of the aryl groups include phenyl and naphthyl. The aryl groupmay have a substituent group such as an alkyl group, a halogen atom, anitro group or a cyano group.

The acyl group may either be an aliphatic acyl group or an aromatic acylgroup. When the acyl group is the aliphatic acyl group, an acyl grouphaving 1 to 7 carbon atoms is preferably used. An acyl group having 2 to5 carbon atoms is more preferred. The acyl group may be straight orbranched chain. Specific examples thereof include acetyl, propionyl,butyryl, isobutyryl, valeryl and pivaloyl. The acyl group may have asubstituent group such as an amino group, a lower alkoxycarbonylaminogroup, a carboxy group or a heterocyclic ring. Specific examples thereofinclude glycyl, alanyl, valyl, prolyl, methionyl, aspartyl, glutamyl,histidyl, N-ethoxycarbonylalanyl, N-t-butoxycarbonylalan-yl. The loweralkoxycarbonyl portion of the lower alkoxycarbonylamino group and theheterocyclic ring include groups described below.

Examples of the aromatic acyl groups include benzoyl, naphthoyl andtoluoyl.

The alkoxycarbonyl group whose alkoxy portion is an alkoxy group having1 to 7 carbon atoms is preferred, and an alkoxy group having 1 to 4carbon atoms is more preferred. The alkoxy portion may be straight orbranched. Specific examples thereof include methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl. The alkoxy portionmay be an aromatic alkoxy group such as benzyloxycarbonyl.

An example of the heterocyclic ring formed by R₃, R₄ and the nitrogenatom bound thereto is a heterocyclic ring formed with an alkylene groupor an alkenylene group constituted by R₃ and R₄. The alkylene grouppreferably has 2 to 5 carbon atoms, and may be straight or branchedchain. Specific examples thereof include methylene, ethylene,trimethylene, propylene, tetramethylene and 1,2-dimethylethylene.Examples of the alkenylene groups include 1-butenylene and1,3-butadienylene. Specific examples of these heterocyclic groupsinclude pyrrolidinyl, piperidino, pyrrolinyl and pyrrolyl.

The heterocyclic ring may be formed by R₃, R₄ and the nitrogen atom towhich R₃ and R₄ are bound, through a second heteroatom (for example,nitrogen, oxygen or sulfur). Examples of these heterocyclic groupsinclude piperazinyl, morpholino, thiomorpholino, imidazolinyl,imidazolidinyl, imidazolyl and pyrazolidinyl. In particular, imidazolylor a group represented by the following formula: ##STR3## wherein R₅represents H, alkyl, acyl, aryl or alkoxycarbonyl as above defined; ispreferably used. Examples of the alkyl, acyl, aryl and alkoxycarbonylgroups represented by R₅ include the groups described above.

It is particularly preferred that substituent group R₁ and substituentgroup --NH--C(═Z)--NHR₂ are bound to the pyridine skeleton at the6-position and 3-position, 2-position and 5-position, 4-position and3-position or 4-position and 5-position, respectively.

When the aminopyridine compounds of the present invention haveasymmetric carbon atoms, optical isomers thereof and the mixture of theoptical isomers are included in the scope of the present invention.

The compounds of the present invention can be prepared, for example, bythe following methods, although they can be synthesized by other methodsapparent to the skilled artisan. ##STR4## wherein R₁ and R₂ have thesame meanings as given above.

The compound represented by formula (1-1) is obtained by reacting thecompound represented by formula (2) with the compound represented byformula (3). This reaction is usually conducted in a solvent. As such asolvent, any solvent may be used as long as it does not exert an adverseeffect on the reaction. Examples of such solvents include ethers such asdiethyl ether, tetrahydrofuran and dioxane; hydrocarbon halides such asdichloromethane, dichloroethane, chloroform and carbon tetrachloride;aromatic hydrocarbons such as benzene, toluene and xylene; amines suchas pyridine and piperidine; and aprotic polar solvents such asdimethylformamide (DMF) and dimethyl sulfoxide.

The amount of the compound of formula (3) to the compound represented byformula (2) is about 0.9 to 5 times, and preferably about equimolar to 3times the molar quantity of the compound represented by formula (2).

This reaction is conducted at about 10° to 80° C., preferably at roomtemperature (namely, about 15° to 25° C.), for about 1 to 200 hours.##STR5## wherein R₁ and R₂ have the same meanings as given above.

First Step

In the first step of this reaction process, the compound represented byformula (2) is reacted with the compound represented by formula (4) toobtain the compound represented by formula (5). This reaction is usuallyconducted in a solvent. As such a solvent, any solvent may be used aslong as it has no adverse effect on the reaction. Examples of suchsolvents include the solvents described above. In particular, the polarsolvents such as pyridine, dimethylformamide (DMF) and dimethylsulfoxide are suitably used.

The amount of the compound of formula (4) used to the compoundrepresented by formula (2) is about 0.9 to 5 times, and preferably aboutequimolar to twice the molar quantity of the compound represented byformula (2).

This reaction is conducted at about 10 to 80° C, preferably at roomtemperature (namely, about 15 to 25° C), for about 1 to 200 hours.

Second Step

In the second step, the compound represented by formula (6) is reactedwith the compound of formula (5) obtained above to obtain the compoundrepresented by formula (1-2). This reaction may be conducted in asolvent or in a solvent-free state. As such a solvent, any solvent maybe used as long as it has no adverse effect on the reaction. Forexample, polar solvents such as dimethylformamide (DMF) and dimethylsulfoxide are suitably used.

The amount of the compound of formula (6) used to the compoundrepresented by formula (5) is about 0.9 to 10 times, and preferablyabout equimolar to 3 times the molar quantity of the compoundrepresented by formula (5).

This reaction is conducted at about 10° to 90° C. for about 1 to 100hours.

When R₁ is not NH₂, the raw material compound represented by formula (2)can be prepared by the following method. ##STR6## wherein R₁ has thesame meaning as given above.

First Step

In the first step of this reaction process, the compound represented byformula (7) is reacted with the compound represented by formula (8) toobtain the compound represented by formula (9). This reaction is usuallyconducted in a solvent. As such a solvent, any solvent may be used aslong as it has no adverse effect on the reaction. Examples of suchsolvents include the solvents described above. It is preferred that thisreaction is conducted in the presence of a basic substance. Examples ofsuch basic substances include triethylamine, tributylamine,1,5-diazabicyclo[4.3.0]nonene-5 (DBN) and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU).

The amount of the compound of formula (8) used to the compoundrepresented by formula (7) is about 0.9 to 5 times, and preferably aboutequimolar to 3 times the molar quantity of the compound represented byformula (7). The amount of the basic substance used is about equimolarto 5 times, and preferably about 1.5 to 3 times the molar quantity ofthe compound represented by formula (7).

This reaction is conducted at about 10° to 100° C. for about 5 minutesto 50 hours.

Second Step

In the second step, the nitro group of the compound of formula (9)obtained above is reduced to obtain the compound represented by formula(2-1). This reaction can be conducted by any method as long as a nitrogroup is converted into a an amino group, and is usually conducted bycatalytic reduction in the presence of a appropriate reduction catalyst.Examples of such reduction catalysts include platinum oxide, palladiumblack, palladium carbon and Raney nickel. These reduction catalysts aregenerally used in an amount of about 0.1 to 0.5 times the weight of thecompound represented by formula (9).

This catalytic reduction is conducted in a solvent such as ethanol,dioxane, tetrahydrofuran and chloroform, in a hydrogen atmosphere ofordinary pressure to about 5 kg/cm² at about 10° to 40° C., preferablyat room temperature (namely, about 15° to 25° C.) for about 1 to 30hours. ##STR7## wherein R₃ and R₄ have the same meanings as given above.

First Step

In the first step of this reaction process, the compound represented byformula (7) is reacted with the compound represented by formula (10) toobtain the compound represented by formula (11). This reaction isconducted in a solvent-free state or in a solvent. As such a solvent,any solvent may be used as long as it has no adverse effect on thereaction. Examples of such solvents include the solvents describedabove. It is preferred that this reaction is conducted using thecompound of formula (10) in excess or in the presence of a basicsubstance. Examples of such basic substances include the substancesdescribed above.

The amount of the compound of formula (10) used to the compoundrepresented by formula (7) is about 0.9 to 5 times, and preferably aboutequimolar to 3 times the molar quantity of the compound represented byformula (7). The amount of the basic substance used is about equimolarto 5 times, and preferably about 1.5 to 3 times the molar quantity ofthe compound represented by formula (7).

This reaction is conducted at about 50° to 140° C. for about 1 to 50hours.

Second Step

In the second step, the carboxylic acid compound represented by formula(12) or in which compound the carboxyl group is activated is reactedwith the compound of formula (11) obtained above to obtain the compoundrepresented by formula (9-1). This reaction can be conducted inaccordance with conventional amide forming reaction methods such asmethods using condensing agents (for example, DCC), mixed acid anhydridemethods, active esterification methods and methods using carboxylic acidhalides. This reaction is usually conducted in a solvent. As such asolvent, any solvent may be used as long as it has no adverse effect onthe reaction. Examples of such solvents include the solvents describedabove. When the methods using carboxylic acid halides are employed, itis preferred that the reaction is conducted in the presence of basicsubstances. Examples of the basic substances include the above-describedbasic substances and basic alkaline metal salts.

The amount of the compound of formula (12) used to the compoundrepresented by formula (11) is about 0.9 to 5 times, and preferablyabout equimolar to twice the molar quantity of the compound representedby formula (11). The amount of the basic substance used is aboutequimolar to 5 times, and preferably about 1.5 to 3 times the molarquantity of the compound represented by formula (11). This reaction isconducted under ice cooling or at up to about 80° C. for 1 minute to 30hours. ##STR8## wherein R₁, R₂ and Z have the same meanings as givenabove

The compound represented by formula (1-4) is obtained by oxidation ofthe compound represented by formula (1-3) using an oxidant. Thisreaction is usually conducted in a solvent. Any solvent may be used inthis reaction as long as it does not exert an adverse effect on thereaction. Examples of the solvents include hydrocarbon halides such asdichloromethane, dichloroethane, chloroform and carbon tetrachloride;alcohols such as methanol and ethanol; aromatic hydrocarbons such asbenzene, toluene and xylene; and fatty acids such as acetic acid andpropionic acid. Examples of the oxidant used in this reaction includeperacetic acid, perbenzoic acid, m-chloroperbenzoic acid and hydrogenperoxide.

The amount of the oxidant is about 0.9 to 2 times, preferably aboutequimolar to 1.2 times the molar quantity of the compound represented byformula (1-3).

This reaction is conducted under ice cooling or at up to roomtemperature for 1 to 10 hours. ##STR9## wherein R₁ and R₂ have the samemeanings as given above.

First Step

The first step of this reaction process is conducted in an organicsolvent such as dichloromethane, preferably in the presence of mercuricoxide, sulfur, triphenylphosphine, carbon tetrachloride or triethylamineat 30° to 60° C. for 10 to 100 hours.

Second Step

The second step of this reaction process is conducted in an organicsolvent such as ether, preferably in the presence ofdiisopropylethylamine at 10° to 30° C. for 1 to 50 hours.

The novel compound (1) of the present invention thus produced can becollected as a product of arbitrary purity, appropriately using knownseparation and purification techniques such as concentration,extraction, chromatography, reprecipitation and recrystallization.

The compound (1) of the present invention has a basic group, so that itcan be converted to the acid salt by techniques known in the art. Thereis no particular restriction on such a salt, as long as it ispharmaceutically acceptably non-toxic. Examples of such salts includeinorganic acid salts (for example, hydrochlorides, hydrobromides,phosphates and sulfates) and organic acid salts (for example, acetates,succinates, maleates, fumarates, malates and tartrates).

The compounds (1) and the acid salts thereof of the present inventionare very non-toxic, and have strong, sustained hypotensive, peripheralvasodilative, coronary vasodilative and cerebal vasodilative activitiesin mammals (for example, mice, rats, rabbits, dogs, cats and humans).They are therefore useful as prophylactic or therapeutic agents forcirculatory diseases such as hypertension, ischemic heart diseases (forexample, angina pectoris and myocardinal infarction) and cerebral andperipheral circulatory afflictions (for example, cerebral infarction andtransient cerebral ischemic attack).

In particular, the compounds (1) and the acid salts thereof of thepresent invention are excellent in both the potency of thepharmacological action and the persistency thereof, compared to theconventional compounds having similar structures (for example,Pinacidil). For example, when they are used as prophylactic ortherapeutic agents for hypertension, a stable hypotensive activity canbe obtained by infrequent administration (once or twice a day).

Further, the compounds of the present invention are superior in abeneficial effect on blood lipids to Pinacidil. Therefore, the compoundsof the present invention are expected to be useful for not onlyamelioration of lipometabolism but also relaxation of smooth muscleinvolved in gastrointestinal tract, respiratory system and uterus.

When the compounds (1) and the acid salts thereof of the presentinvention are used as the above-described drugs, pharmaceuticallyacceptable additives such as carriers, excipients and diluents are mixedwith pharmaceutically required components to prepare medicalcompositions in powder, granule, tablet, capsule or injection form,which can be given orally or parenterally. The compounds (1) and theacid salts thereof of the present invention are contained in effectiveamounts thereof in the above-described preparations. The dosage variesdepending on the administration route, the symptom, and the weight orthe age of the patient. For example, when the preparations are orallygiven to adult patients with hypertension, it is desirable that thepatients are dosed with 0.05 to 20 mg/kg of body weight/day, preferablywith 0.1 to 4 mg/kg of body weight/day, administered once or in severaldivided doses.

The invention will be illustrated in more detail by reference to thefollowing examples, but the invention is not limited to these examples.

EXAMPLE 1 (4-amino-3-pyridyl)thiourea hydrochloride

Thirty milliliters of concentrated hydrochloric acid was cooled withice, and 3,4-diaminopyridine (10.0 g, 91.6 mmol) was added thereto.Then, the mixture was heated at 50° to 60° C. for 10 to 15 minutes, andthereafter excess hydrochloric acid was removed by distillation underreduced pressure. Ammonium thiocyanate (13.1 g, 0.17 mol) dissolved in15 ml of water was added to the residue, followed by reaction at 80° C.for 4 hours. The reaction product was cooled to room temperature, and aprecipitated solid was collected by filtration. The solid was washedwith water and acetone, and dried to obtain a white solid (yield: 16.0g).

IR (KBr): 3250, 3100, 3000, 1630 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.67 (1H, s), 8.40 (1H, s), 8.04 (1H, d, J=6.8Hz), 8.35-7.45 (4H, brs), 6.96 (1H, d, J=7.2 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 183.18, 156.00, 138.48, 137.10, 121.02, 109.43

EXAMPLES 2 To 8

3,4-Diaminopyridine (2 g, 18.3 mmol) was suspended in anhydrous pyridine(10 ml) under an atmosphere of nitrogen. Each of the isothiocyanates(R-NCS) shown in Table 1 was added dropwise thereto, followed bystirring. After removal of pyridine by distillation under reducedpressure, the reaction mixture was purified. When R is t-Bu, cyclo-Hexor CH(CH₃)C(CH₃)₃, the product was precipitated as a white powder. Thepowder was collected by filtration, and then washed with ether, followedby drying. Reaction conditions, purification methods and yields areshown in Table 1.

                  TABLE 1                                                         ______________________________________                                                                    Reac-                                             Ex-               Isothio-  tion        Purifi-                               am-               cyanate   Time  Yield cation                                ple  R            (g, mmol) (hr)  (%)   Method                                ______________________________________                                        2    Me.sup.1     (5.0, 68.7)                                                                             14    94    A                                     3    Et           (4.8, 55.0)                                                                             21    quanti-                                                                             B                                                                       tative                                      4    n-Pr         (1.8, 18.3)                                                                             5 days                                                                              76    B                                     5    n-Bu         (6.3, 55.0)                                                                             42    quanti-                                                                             B                                                                       tative                                      6    t-Bu         (6.3, 55.0)                                                                             7 days                                                                              93    C                                     7    c-C.sub.5 H.sub.11                                                                         (7.7, 55.0)                                                                             40    93    C                                     8    CH(CH.sub.3)C(CH.sub.3).sub.3                                                              (4.1, 28.8)                                                                             5 days                                                                              96    C                                     ______________________________________                                         .sup.1 Diaminopyridine (3 g, 27.5 mmol) was used.                             A: Ether (20 ml) was added to the concentrated residue, and the resulting     precipitate was collected by filtration.                                      B: The concentrated residue was purified by flash column chromatography       (silica gel: 400 g/methanol).                                                 C: The precipitated powder was collected by filtration.                  

The properties of the compounds obtained in Examples 2 to 8 and methodsfor preparation of the salts thereof are shown below.

EXAMPLE 2 (a) N-(4-amino-3-pyridyl)-N'-methylthiourea

IR (KBr): 3200, 1620, 1540, 1260 cm⁻¹

¹ H-NMR (CDCl₃ : MeOH-d₄ =4:1) δppm: 8.02 (1H, d, J=5.6 Hz), 8.00 (1H,s), 6.68 (1H, d, J=5.6 Hz), 3.07 (3H, s)

(b) N-(4-amino-3-pyridyl)-N'-methylthiourea hydrochloride

Methanol (10 ml) was added to N-(4-amino-3-pyridyl)-N'-methylthiourea(1.02 g, 5.60 mmol) to prepare a homogeneous solution. Then,hydrochloric acid-ethanol (1.75 N, 3.2 ml) was added dropwise theretounder ice cooling and the resulting solution was stirred for 1 hour. Aprecipitate produced in the reaction mixture was collected byfiltration, and dried at the reflux temperature of dichloromethane usinga crystal dryer to obtain a monohydrochloride (816 mg) as a whitepowder.

m.p.: 278°-280° C.

IR (KBr): 3200, 1640, 1550, 1250 cm⁻¹

¹ H-NMR (D₂ O) δppm: 8.14 (1H, s), 8.04 (1H, dd, J=1.0 Hz, 7.0 Hz), 7.03(1H, d, J=7.0 Hz), 3.04 (3H, s)

¹³ C-NMR (D₂ O) δ ppm: 184.66, 160.69, 143.16, 141.35, 121.83, 112.84,34.32

EXAMPLE 3 N-(4-amino-3-pyridyl)-N'-ethylthiourea White powder

IR (KBr): 3200, 1640, 1540 cm⁻¹

¹ H-NMR (DMSO-d₆) δppm: 9.20 (1H, s), 8.06 (1H, s), 8.06 (1H, s), 7.92(1H, d, J=5.8 Hz), 6.70 (1H, d, J=5.8 Hz), 6.28 (2H, s), 3.45 (2H, q,J=6.3 Hz), 1.10 (3H, t, J=7.1 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.73, 152.89, 143.21, 141.65, 120.76,109.45, 38.88, 14.02

EXAMPLE 4 N-(4-amino-3-pyridyl)-N'-n-propylthiourea White powder

IR (KBr): 3200, 1620, 1530, 1260 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.71 (1H, s), 7.91 (1H, s), 7.90 (1H, d, J=5.5Hz), 7.51 (1H, s), 6.62 (1H, d, J=5.5 Hz), 5.70 (2H, s), 3.39 (2H, m),1.54 (2H, sext, J=7.2 Hz), 0.87 (3H, t, J=7.4 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.66, 150.47, 148.93, 147.22, 119.95,109.72, 45.91, 21.85, 11.31

EXAMPLE 5 N-(4-amino-3-pyridyl)-N'-n-butylthiourea White powder

IR (KBr): 3200, 1620 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.50 (1H, s), 8.37 (1H, s), 8.37 (1H, s), 7.97(1H, d, J=6.1 Hz), 6.91 (2H, s), 6.83 (1H, d, J=6.1 Hz), 3.45 (2H, m),1.59-1.25 (4H, m), 0.90 (3H, t, J=7.2 Hz) ¹³ C-NMR (DMSO-d₆) δ ppm:182.13, 152.78, 143.33, 141.83, 120.98, 109.52, 43.89, 30.64, 19.68,13.81

EXAMPLE 6 (a) N-(4-amino-3-pyridyl)-N'-t-butylthiourea White powder

IR (KBr): 3500, 2950, 1620, 1530, 1270 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.53 (1H, s), 7.94 (1H, s), 7.88 (1H, d, J=5.5Hz), 7.22 (1H, s), 6.61 (1H, d, J=5.5 Hz), 5.70 (2H, s), 1.47 (9H,s)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.02, 150.44, 149.26, 147.06, 120.66,109.75, 52.72, 28.67

(b) N-(4-amino-3-pyridyl)-N'-t-butylthiourea dihydrochloride

Water (5 ml) was added to N-(4-amino-3-pyridyl)-N'-t-butylthiourea (962mg, 4.29 mmol) to suspend it. 1 N aqueous solution of hydrochloric acid(8.58 ml) was added thereto, and the mixture was heated in a hot waterbath until a homogeneous solution was obtained, followed by removal ofwater by distillation. The resulting white crystal was dried at thereflux temperature of dichloromethane using a crystal dryer to obtain adihydrochloride (1.12 g) as a white powder. m.p.: >250° C.

IR (KBr): 3150, 1640, 1550, 1260 cm⁻¹

EXAMPLE 7 N-(4-amino-3-pyridyl)-N'-cyclohexylthiourea White powder

IR (KBr): 3400, 1640, 1560 cm⁻¹

H-NMR (DMSO-d₆) δ ppm: 9.70 (1H, s), 8.58 (1H, d, J=7.6 Hz), 8.51 (1H,s), 8.03 (1H, d, J=6.7 Hz), 7.91 (1H, s), 6.96 (1H, d, J=6.7 Hz), 1.91(2H, m), 1.70-1.56 (3H, m), 1.26 (5H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.83, 155.54, 138.16, 136.98, 121.24,109.25, 52.48, 31.74, 24.21, 25.17

EXAMPLE 8 N-(4-amino-3-pyridyl)-N'-(1,2,3-trimethylpropyl)thiourea

¹ H-NMR (DMSO-d₆) δ ppm: 8.66 (1H, bs), 7.96 (1H, s), 7.89 (1H, d, J=5.5Hz), 7.13 (1H, d, J=8.6 Hz), 6.62 (1H, d, J=5.5 Hz), 5.67 (2H, bs), 4.29(1H, m), 1.05 (3H, d, J=6.7 Hz), 0.90 (9H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.81, 150.22, 148.88, 147.06, 120.51,109.67, 57.46, 34.33, 26.19, 15.24

EXAMPLE 9 a) 4-Chloro-3-nitropyridine

Phosphorus oxychloride (25 ml, 0.27 mol) was added to4-hydroxy-3-nitropyridine (7.0 g, 50.0 mmol), followed by reaction at80° to 90° C. for 1.5 hours. Phosphorus oxychloride was removed bydistillation. About 100 g of ice was added to the residue, and 28%aqueous ammonia was added dropwise thereto to adjust the pH to 7. Then,100 ml of water was added thereto, and the aqueous mixture was extractedthree times with 200 ml of dichloromethane. The resultingdichloromethane layer was dried, and then dichloromethane was removed bydistillation under reduced pressure to obtain 7.75 g of a yellow liquid(yield: 97.8%).

(b) 3-Nitro-4-methylaminopyridine

Methylamine hydrochloride (1.55 g, 22.9 mmol) and potassium carbonate(4.22 g, 30.5 mmol) were added to a solution (5 ml) of4-chloro-3-nitropyridine (2.3 g, 15.3 mmol) in dioxane. The mixture wasstirred under reflux for 1.5 hours, at room temperature for 15 hours,and further under reflux for 3 hours. After filtration using Celite, thefiltrate was concentrated and subjected to silica gel columnchromatography (eluent: chloroform) to purify it, whereby 1.52 g of theintended product was obtained.

IR (CHCl₃): 3400, 2980, 1620, 1370 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 3.07 (3H, d, J=4.0 Hz), 6.72 (1H, d, J=6.0 Hz),8.16 (1H, brs), 8.33 (1H, d, J=6.0 Hz), 9.21 (1H, s)

(c) 3-Amino-4-methylaminopyridine

150 mg of platinum oxide was added to 10 ml of a solution of3-nitro-4-methylaminopyridine (1.5 g) in ethanol. The mixture wasstirred under a hydrogen atmosphere at room temperature for 7.5 hours.Platinum oxide was removed by filtration, and the filtrate wasconcentrated. Thus, 962 mg (yield: 80%) of the intended product wasobtained as brown crude crystals.

(d) N-(4-methylamino-3-pyridyl)-N'-cyclohexylthiourea

Cyclohexyl isothiocyanate (1.09 ml, 7.71 mmol) was added to a solutionof 3-amino-4-methylaminopyridine (950 mg, 7.71 mmol) in DMF (5 ml), andthe mixture was stirred at room temperature for 1 hour and at 120° C.for 3 hours. After removal of the solvent, the residue was subjected tosilica gel column chromatography (eluent: chloroform:methanol=10:1(v/v)) and recrystallization to purify it, thereby obtaining 98 mg ofthe intended product as flesh-colored crystals.

m.p.: >250° C.

IR (KBr): 3500-3000, 2920, 1600 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 1.0-2.1 (10H, m), 2.89 (3H, d, J=4.0 Hz), 4.1-4.4(1H, m), 4.93 (1H, d, J=4.0 Hz), 5.72 (1H, d, J=6.0 Hz), 6.56 (1H, d,J=6.0 Hz), 7.65 (1H, s), 8.10 (1H, s), 8.26 (1H, d, J=6.0 Hz)

¹³ C-NMR (CDCl₃) δ ppm: 24.5, 25.1, 28.7, 32.2, 53.8, 105.2, 118.0,147.4, 149.0, 151.7, 179.9

EXAMPLES 10 To 12

Using t-butylamine (Example 10), cyclohexylamine (Example 11) anddiethylamine (Example 12) instead of methylamine used in Example 9 (b),4-substituted amino-3-nitropyridine compounds corresponding thereto,respectively, were obtained. Then, the following correspondingaminopyridine compounds were obtained in accordance with the methods ofExample 9 (c) and (d).

EXAMPLE 10 N-(4-t-butylamino-3-pyridyl)-N'-cyclohexylthiourea

m.p.: 216°-218° C.

IR (KBr): 3500-3100, 2950, 2900, 1610 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 1.0-2.1 (19H, m), 4.1-4.4 (1H, m), 4.87 (1H, s),6.78 (1H, d, J=6.0 Hz), 8.05 (1H, s), 8.13 (1H, d, J=6.0 Hz)

¹³ C-NMR (CDCl₃) δ ppm: 24.6, 24.7, 29.1, 32.5, 51.4, 54.0, 107.3,118.9, 149.5, 180.3

EXAMPLE 11 N-(4-cyclohexylamino-3-pyridyl)-N'-cyclohexylthiourea

m.p.: 157°-159° C.

IR (KBr): 3500-3000, 2900, 2800, 1600 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 1.0-2.1 (20H, m), 3.2-3.4 (1H, m), 4.1-4.4 (1H,m), 4.70 (1H, d, J=8.0 Hz), 5.72 (1H, brs), 6.57 (1H, d, J=6.0 Hz), 7.50(1H, brs), 8.09 (1H, s), 8.19 (1H, d, J=6.0 Hz)

EXAMPLE 12 N-(4-diethylamino-3-pyridyl)-N'-cyclohexylthiourea

m.p. 119°-121° C.

IR (KBr): 2900, 2800, 1595 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 1-2.5 (16H, m), 3.33 (4H, q), 4.1-4.4 (1H, m),6.00 (1H, d, J=8.0 Hz), 6.76 (1H, d, J=6.0 Hz), 7.87 (1H, brs), 8.21(1H, s), 8.23 (1H, d, J=6.0 Hz)

¹³ C-NMR (CDCl₃) δ ppm: 12.7, 24.7, 25.3, 32.6, 45.1, 112.8, 54.2,121.9, 148.9, 150.1, 151.0, 179.4

EXAMPLE 13 (a) 4-(1-Imidazolyl)-3-nitropyridine

4-Chloro-3-nitropyridine (2.00 g, 12.6 mmol) and imidazole (2.25 g, 33.0mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylaminewas added thereto, followed by reaction at 90° to 100° C. for 1.5 hours.Then, the solvent was removed by distillation under reduced pressure,and the residue was purified by silica gel column chromatography[eluent: dichloromethane:methanol=10:1 (v/v)] to obtain 2.31 g of ayellow liquid (yield: 96.4%).

¹ H-NMR (DMSO-d₆) δ ppm: 9.32 (1H, s), 9.00 (1H, d, J=5.3 Hz), 8.08 (1H,s), 7.84 (1H, d, J=5.3 Hz), 7.53 (1H, s), 7.16 (1H, s)

(b) 3-Amino-4-(1-imidazolyl)pyridine

4-(1-Imidazolyl)-3-nitropyridine (2.10 g, 11.0 mmol) was dissolved in 20ml of ethanol. After the atmosphere was replaced with nitrogen, 0.25 gof 10% palladium-carbon was added thereto. After the atmosphere wasreplaced with hydrogen, hydrogen addition was conducted with stirring atroom temperature for 3 days. Palladium-carbon was removed by filtrationand the filtered cake was washed with ethanol. The filtrate and thewashings were combined and then concentrated. The residue was purifiedby silica gel column chromatography [eluent: dichloromethane:methanol=8:1-6:1 (v/v)] to obtain 1.62 g of a light brown solid (yield:91.6%).

¹ H-NMR (DMSO-d₆) δ ppm: 8.25 (1H, s), 7.92 (1H, s], 7.87 (1H, d, J=5.1Hz), 7.44 (1H, s), 7.14 (1H, s), 7.11 (1H, d, J=5.1 Hz), 5.50-5.20 (2H,brs)

(c) N-4-(1-imidazolyl)-3-pyridyl]-N'-cyclohexylthiourea

3-Amino-4-(1-imidazolyl)pyridine (1.00 g, 5.95 mmol) was added to 5 mlof DMF, and cyclohexyl isothiocyanate (2.5 ml, 17.63 mmol) was addedthereto. After reaction at room temperature for 4 days, the reactionsolution was directly purified by column chromatography eluent:dichloromethane:methanol=7:1 (v/v)]. Ether was added to the collectedeffluent to achieve crystallization, and 0.30 g of the precipitatedsolid was collected by filtration (yield: 16.7%).

IR (KBr) 3150, 2900, 2850, 1590, 1550, 1500, 1080 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm:

9.10-8.90 (1H, brs), 8.57-8.50 (2H, s+d), 7.99 (1H, s), 7.98-7.85 (1H,brs), 7.55 (1H, d, J=5.3 Hz), 7.48 (1H, s), 7.11 (1H, s) 4.20-3.80 (1H,brs), 2.00-1.00 (10H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.37, 152.54, 148.49, 140.48, 136.59,129.34, 128.17, 119.04, 118.55, 52.81, 31.71, 25.02, 24.45

EXAMPLE 14 (a) 4-Phenylamino-3-nitropyridine

4-Chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylaminewas added thereto, followed by reaction at 80° to 90° C. for 2 hours.Then, the solvent was removed by distillation under reduced pressure,and 10 ml of hexane was added to the residue to wash it. The solvent wasremoved by decantation. The residue was further similarly treated with10 ml of ether. The residue was purified by silica gel columnchromatography [eluent: hexane:ethyl acetate=2:1 (v/v)]to obtain 1.41 gof a yellow solid (yield: 68.8%).

¹ H-NMR (DMSO-d₆) δ ppm: 9.84 (1H, brs), 9.10 (1H, s), 8.24 (1H, d,J=6.2 Hz), 7.55-7.28 (5H, m), 6.88 (1H, d, J=6.2 Hz)

(b) 3-Amino-4-phenylaminopyridine

4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in themixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. Afterthe atmosphere was replaced with nitrogen, 0.10 g of 10%palladium-carbon was added thereto. After the atmosphere was replacedwith hydrogen, hydrogen addition was conducted with stirring at roomtemperature for about 15 hours. Palladium-carbon was removed byfiltration and the filtered cake was washed with ethanol. The filtrateand the washings were combined and then concentrated. The residue waspurified by silica gel column chromatography [eluent: dichloromethane:methanol=2:1 (v/v)]to obtain 1.07 g of a light brown solid (yield:88.7%).

¹ H-NMR (DMSO-d₆) δ ppm: 7.89 (1H, s), 7.64 (1H, d, J=5.4 Hz), 7.58 (1H,brs), 7.35-6.89 (6H, m), 5.20-4.70 (2H, brs)

(c) N-(4-phenylamino-3-pyridyl)-N'-cyclohexylthiourea

3-Amino-4-phenylaminopyridine (1.00 g, 5.40 mmol) was dissolved in 6 mlof DMF, and cyclohexyl isothiocyanate (1.0 ml, 6.8 mmol) was addedthereto. The temperature was gradually raised, and reaction wasconducted at 60° C. for 1.5 hours. Cyclohexyl isothiocyanate (0.5 ml,3.4 mmol) was further added thereto, followed by reaction at 60° C. for1.5 hours. After removal of the solvent by distillation under reducedpressure, the residue was purified by column chromatography [eluent:ethyl acetate]. The fractions containing the intended product,determined by thin layer chromatography, were subjected torecrystallization from methanol-dichloromethane-ether to obtain 1.23 gof a white solid (yield: 69.8%).

m.p.: 179°-182° C. (decomposed)

IR (KBr): 3150, 2900, 2850, 1590, 1500 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.80-8.70 (1H, brs), 8.30-8.15 (1H, brs), 8.04(1H, d, J=5.6 Hz) 7.90 (1H, s), 7.80-7.55 (1H, brs), 7.45-6.90 (6H, m),4.20-3.90 (1H, brs), 2.10-1.10 (10H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.57, 149.17, 147.05, 146.08, 140.37,129.15, 123.35, 122.84, 120.98, 108.50, 52.71, 31.90, 25.13, 24.53

(d) N-(4-phenylamino-3-pyridyl)-N'-cyclohexylthiourea hydrochloride

N-(4-phenylamino-3-pyridyl)-N'-cyclohexylthiourea (1.13 g, 3.46 mmol)was dissolved in 50 ml of ethanol, and 1.2 N hydrogen chloride-ethanol(3.0 ml, 3.6 mmol) was added thereto, followed by removal of the solventby distillation. Then, ether was added to the residue to performsolidification, and thereafter removed by decantation. The resultingsolid was dried to obtain 1.04 g of a white solid (yield: 82.8%).

IR (KBr): 3300, 2900, 1640, 1590, 1510 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 15.4-13.1 (1H, brs), 9.93 (1H, brs), 9.87 (1H,brs), 8.70 (1H, s), 8.57 (1H, brd, J=7.7 Hz), 8.14 (1H, d, J=7.0 Hz),7.60-7.25 (5H, m), 7.05 (1H, d, J=6.9 Hz), 4.20-4.00 (1H, brs),2.10-1.10 (10H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.70, 152.27, 138.10, 137.47, 137.07,129.64, 126.58, 124.40, 123.23, 106.97, 52.49, 31.69, 25.16, 24.18

EXAMPLE 15 (a) 4-Pyrrolidine-1-yl-3-nitropyridine

4-Chloro-3-nitropyridine (2.02 g, 12.7 mmol) was suspended in 15 ml of1,4-dioxane. The suspension was cooled a little in an ice bath, and thenpyrrolidine (2.1 ml, 25.3 mmol) was added dropwise thereto. Thetemperature of the suspension was returned to room temperature, and thesuspension was stirred for 30 minutes, followed by removal of thesolvent by distillation under reduced pressure. The residue was purifiedby silica gel column chromatography (eluent: ethyl acetate) to obtain2.34 g of a yellow solid (yield: 95.4%).

¹ H-NMR (CDCl₃) δ ppm: 8.72 (1H, s), 8.23 (1H, d, J=6.2 Hz), 6.70 (1H,d, J=6.2 Hz), 3.40-3.20 (4H, m), 2.10-1.95 (4H, m)

(b) 3-Amino-4-pyrrolidine-1-yl-pyridine

4-pyrrolidine-1-yl-3-nitropyridine (2.10 g, 10.9 mmol) was dissolved in40 ml of 1,4-dioxane. After the atmosphere was replaced with nitrogen,0.42 g of 10% palladium-carbon was added thereto. After the atmospherewas replaced with hydrogen, hydrogen addition was conducted withstirring at room temperature for about 15 hours. Palladium-carbon wasremoved by filtraton and the filtered cake was washed with 1,4-dioxane.The filtrate and the washings were combined and then concentrated toobtain 1.61 of a brown liquid (yield: 90.7%).

¹ H-NMR (DMSO-d₆) δ ppm: 7.80 (1H, s), 7.65 (1H, d, J=5.2 Hz), 6.53 (1H,d, J=5.3 Hz), 4.70-4.20 (2H, brs), 3.30-3.10 (4H, m), 2.00-1.75 (4H, m)

(c) N-(4-pyrrolidine-1-yl-3-pyridyl)-N'-cyclohexylthiourea

3-Amino-4-pyrrolidine-1-yl-pyridine (1.55 g, 5.40 mmol) was dissolved in10 ml of dichloromethane, and cyclohexyl isothiocyanate (2.6 ml, 18.3mmol) was added thereto. Since a solid was precipitated, 2 ml of DMF wasadded thereto to dissolve the solid, and 2 ml of triethylamine wasfurther added, followed by reaction at room temperature for 3 days. Thesolvent was removed by distillation under reduced pressure, and then theresidue was purified by column chromatography [eluent:dichloro-methane:methanol=10:1-8:1 (v/v)]. The collected solid wasrecrystallized from dichloromethane to obtain 1.21 g of a light yellowsolid (yield: 41.8%).

IR (KBr): 3150, 2950, 2850, 1600, 1510 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.00-8.60 (1H, brs), 7.97 (1H, d, J=5.8 Hz),7.86 (1H, s), 7.40-6.80 (1H, brs), 6.51 (1H, d, J=5.9 Hz), 4.25-3.90(1H, brs), ca. 3.4 (4H), 2.10-1.00 (14H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 181.20, 151.44, 149.78, 147.66, 119.34,109.08, 52.65, 48.39, 32.00, 25.07, 24.56

EXAMPLE 16 (a) 3-Nitro-4-aminopyridine

Five grams (31.5 mmol) of 3-nitro-4-chloropyridine was mixed with 26 gof ammonium acetate, and the mixture was heated at 130-140° C. for 3hours. The mixture was allowed to cool, and then adjusted to pH 10 withconcentrated aqueous ammonia. The precipitated powder was collected byfiltration to obtain 2.6 g of the intended yield: 59%).

(b) 3-Nitro-4-acetylaminopyridine

In 6 ml of pyridine, 1.2 g (8.63 mmol) of the amino compound of theabove-described compound (a) was suspended, and then 0.65 ml (8.63 mmol)of acetyl chloride was gradually added under ice cooling. After reactionat room temperature for 24 hours, the solvent was removed bydistillation. The residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=50:1) to obtain 1.12 g ofthe intended product (yield: 72%).

IR (KBr): 3350, 1720, 1600, 1350 cm⁻¹

(c) 3-Amino-4-acetylaminopyridine

To 40 ml of a solution of the acetylamide compound (1 g) of theabove-described compound (b) in ethanol was added 200 mg of 10%palladium-carbon, followed by reaction in an atmosphere of hydrogen atroom temperature for 24 hours. Palladium-carbon was removed byfiltration, and then the solvent was removed by distillation to obtainthe intended product (900 mg).

IR (KBr) 3300, 1695 cm⁻¹

(d) N-cyclohexyl-N'-(4-acetylamino-3-pyridyl)thiourea

To 10 ml of a solution of the acetylamino compound (0.9 g, 5.95 mmol) ofthe above-described compound (c) in pyridine was added 0.84 ml (5.95mmol) of cyclohexyl isothiocyanate, followed by reaction at roomtemperature for 48 hours and at 50°-60° C. for 14 hours. The solvent wasremoved by distillation, and the residue was washed with methanol toobtain 1 g of the intended product (yield: 57%).

IR (KBr): 3200, 2850, 1680 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.61 (1H, bs), 8.61 (1H, bs), 8.48 (1H, s),8.25 (1H, d, J=5.4 Hz), 7.97 (1H, d, J=5.2 Hz), 7.79 (1H, d, J=5.4 Hz),4.07 (1H, m), 2.13 (3H, s), 1.96-1.92 (2H, m), 1.70-1.57 (3H, m),1.34-1.17 (5H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.67 (s), 169.32 (s), 149.73 (d), 146.46(d), 140.12 (s), 126.54 (s), 116.06 (d), 52.89 (d), 31.84 (t), 25.12(t), 24.56 (t), 23.93 (q)

EXAMPLE 17 N-cyclohexyl-N'-(4-benzoylamino-3-pyridyl)thiourea

The above-described compound was synthesized in accordance with themethod described in Example 16 except for using benzoyl chloride inplace of acetyl chloride used in Example 16(b).

IR (KBr): 3200, 2900, 1650 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.89 (1H, bs), 8.85 (1H, bs), 8.52 (1H, s),8.39 (1H, d, J=5.4 Hz), 8.15 (1H, bs), 7.95 (2H, d, J=6.9 Hz), 7.85 (1H,d, J=5.4 Hz), 7.68-7.51 (3H, m), 4.10 (1H, bs), 1.92 (2H, m), 1.67-1.55(3H, m), 1.33-1.21 (5H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.48 (s), 165.34 (s), 149.42 (d), 147.18(d), 140.54 (s), 133.62 (s), 132.29 (d), 128.56 (d), 127.56 (d), 117.08(d), 52.90 (d), 31.76 (t), 25.05 (t), 24.47 (t)

EXAMPLE 18 N-(2-amino-3-pyridyl)-N'-cyclohexylthiourea

2,3-Diaminopyridine (1.00 g, 9.16 mmol) was dissolved in 5 ml ofpyridine, and cyclohexyl isothiocyanate (4.2 ml, 29.6 mmol) was addedthereto. After reaction at room temperature for 4 days, pyridine wasremoved by distillation, and the residue was purified by silica gelcolumn chromatography [eluent: chloroform: methanol=10:1 (v/v)].Recrystallization from ethanol-ether-hexane gave 1.06 g of the intendedproduct as white crystals (yield: 46.2%).

m.p.: 159°-160° C. (decomposed)

IR (KBr): 3350, 3250, 3100, 2900, 2850, 1630, 1520, 1500, 1460 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm 8.50 (1H, brs), 8.00 (1H, dd, J=5.0, 1.7 Hz), 7.36(1H, dd, J=7.6, 1.6 Hz), 6.68 (1H, dd, J=7.6, 5.0 Hz), 5.70-5.55 (1H,brd), 5.50-4.90 (2H, brs), 4.33-4.10 (1H, brt), 2.10-0.95 (10H, m)

¹³ C-NMR (CDCl₃): δ ppm: 179.30, 155.68, 148.11, 136.62, 116.14, 114.28,53.99, 32.46, 25.22, 24.62

EXAMPLES 19 And 20

Using 3,5-diaminopyridine (Example 19) and 2,5-diaminopyridine (Example20) in place of 2,3-diaminopyridine, the following compounds weresynthesized in accordance with the method described in Example 18.

EXAMPLE 19 N-(5-amino-3-pyridyl)-N'-cyclohexylthiourea

m.p.: 114°-116° C.

IR (KBr): 3600-3000, 2900, 2850, 1600 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 1.0-2.0 (10H, m), 3.9-4.2 (1H, m), 5.31 (2H,brs), 7.21 (1H, s), 7.65 (1H, s), 7.66 (1H, s), 7.68 (1H, s), 9.19 (1H,s)

¹³ C-NMR (DMSO-d₆) δ ppm: 24.5, 25.1, 31.8, 52.1, 114.0, 131.7, 136.4,144.6, 179.3

EXAMPLE 20 N-(6-amino-3-pyridyl)-N'-cyclohexylthiourea

m.p.: 147°-149° C.

IR (KBr): 3500-3000, 2900, 2850, 1630, 1600 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 1.0-2.0 (10H, m), 3.40 (1H, brs), 4.05 (1H,brs), 5.80 (2H, brs), 6.41 (1H, d, J=8.0 Hz), 7.30 (1H, dd, J=2.0 Hz,8.0 Hz), 7.74 (1H, d, J=2.0 Hz), 8.85 (1H, brs)

¹³ C-NMR (DMSO-d₆) δ ppm: 24.5, 25.1, 31.9, 52.3, 107.2, 125.1, 135.4,144.4, 157.3, 180.4

EXAMPLE 21 N-(6-amino-3-pyridyl)-N'-1,2,2-trimethylpropylthiourea

Using 2,5-diaminopyridine in place of 3,4-diaminopyridine, theabove-described compound was synthesized in accordance with the methoddescribed in Example 8.

IR (KBr) 3300, 2950, 1500 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.85 (9H, s), 1.08 (3H, d, J=6.7 Hz), 4.39 (1H,m), 4.80 (2H, brs), 5.55 (1H, d, J=9.3 Hz), 6.55 (1H, d, J=8.6 Hz),7.25-7.40 (1H, m), 7.73 (1H, brs), 7.95 (1H, d, J=2.6 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 15.3 (q), 26.3 (q), 34.3 (s), 57.2 (d), 107.2(d), 125.2 (s), 135.4 (d), 144.3 (d), 157.3 (s), 181.6 (s)

EXAMPLE 22 (a) S-methyl-N-(4-amino-3-pyridyl)-N'-cyanoisothiourea

3,4-Diaminopyridine (4 g, 36.6 mmol) was suspended in anhydrous pyridine(100 ml), and S,S'-dimethyl N-cyanodithioiminocarbonate (8.0 g, 55.0mmol) was added thereto. The mixture was stirred at room temperature for4 days. The resulting powder was collected from the reaction mixture byfiltration, and washed with ether (100 ml) to obtain crude crystals. Thecrystals were purified by recrystallization from methanol-ether toobtain 1.91 g of the intended product as a white powder (yield: 58%). Onthe other hand, the filtrate was concentrated under reduced pressure,and the residue was purified by flash column chromatography (silica gel,eluent: chloroform:methanol=4:1 (v/v)) to obtain 2.8 g of the intendedproduct (total yield: 95%).

(b) N"-cyano-N'-(4-amino-3-pyridyl)-N-cyclohexylcuanidine

Cyclohexylamine (15 ml) was added to the methylthio compound (2.0 g,9.65 mmol) obtained in (a). The mixture was stirred at room temperaturefor 6 hours, followed by heating to 70° C., and further stirred for 24hours. Excess cyclohexylamine was removed from the reaction mixture bydistillation under reduced pressure, and then the residue was purifiedby recrystallization from methanol-ether to obtain 1.4 g of the intendedproduct as a white powder (yield: 56%). Recrystallization frommethanol-ether was further conducted.

IR (KBr): 3300, 3150, 2900, 2190, 1630 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.22 (1H, s), 7.90 (1H, d, J=5.5 Hz), 7.84 (1H,s), 6.60 (1H, d, J=5.5 Hz), 5.19 (2H, s), 3.59 (1H, m), 1.06-1.80 (10H,m)

¹³ C-NMR (DMSO-d₆) δ ppm: 157.68, 150.66, 148.69, 147.57, 117.94,117.41, 109.66, 50.45, 32.10, 24.96, 24.69

EXAMPLE 23 (a) 4-Amino-3-(1-methylthio-2-nitroethenylamino)pyridine

3,4-Diaminopyridine (6.00 g, 55.0 mmol) and 1,1-bismethylthio)-2-nitroethylene (10.0 g, 60.5 mmol) were dissolved in 60 mlof DMF and 10 ml of triethylamine, followed by reaction at 70° C. for 5hours. The solvent was removed by distillation under reduced pressure,and the residue was purified by silica gel column chromatography[eluent: chloroform:methanol=2:1 (v/v)] to obtain 1.63 g of the intendedproduct (yield: 13.1%)

¹ H-NMR (DMSO-d₆) δ ppm: 8.00-7.87 (1H, brd), 7.75-7.85 (1H, brs),6.60-6.85 (3H, brs+d), 6.53 (1H, s), 2.35 (3H, s)

(b) 4-Amino-3-(1-cyclohexylamino-2-nitroethenylamino)-pyridine

The compound obtained in (a) described above (1.60 g, 7.70 mmol) andcyclohexylamine (8.0 ml, 69.9 mmol) were heated at 80° C. for 2 hours,followed by removal of excess amine by distillation. The residue waspurified by silica gel column chromatography [eluent: chloroform:methanol=2:1 (v/v)] (crude product: 1.0 g). The crude product waspurified by HPLC (column: ODP-90 manufactured by Asahi Chemical IndustryCo. Ltd., detection: 254 NM eluent: water: methanol=1:1 (v/v) tomethanol) to obtain 180 mg of the intended product as a yellow solid(yield: 9.1%).

IR (KBr): 3400, 3200, 2900, 1600, 1540, 1390 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 10.50-10.0 (1H, brs), 9.00-8.40 (1H, brs), 7.98(1H, d, J=5.6 Hz), 7.89 (1H, s), 6.66 (1H, d, J=5.6 Hz), 6.34-6.14 (2H,brs), 5.88-5.68 (1H, brs), 3.85-3.65 (1H, brs), 2.10-1.15 (10H, m)

¹³ C-NMR (DMSO-d₆) δ ppm: 155.78, 151.38, 148.97, 148.37, 117.16,109.41, 97.84, 49.12, 32.12, 24.83, 23.95

EXAMPLE 24 N"-cyano-N-(6-amino-3-pyridyl)-N'-cyclohexylquanidine

Using 2,5-diaminopyridine in place of 3,4-diaminopyridine, theabove-described compound was synthesized in accordance with the methoddescribed in Example 22.

Bright yellow crystals

m.p.: 194°-196° C.

IR (KBr): 3600-3000, 2900, 2850, 2150, 1590 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 1.0-2.0 (10H, m), 3.4-3.8 (1H, m), 5.93 (2H,brs), 6.42 (1H, d, J=8.0 Hz), 6.53 (1H, d, J=8.0 Hz), 7.19 (1H, dd,J=1.0 Hz, 8.0 Hz), 7.70 (1H, d, J=1.0 Hz), 8.30 (1H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 24.8, 25.0, 32.1, 50.4, 107.8, 117.9, 122.8,135.6, 145.2, 158.0

EXAMPLE 25N"-cyano-N-(6-amino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)-guanidine

Using 1,2,2-trimethylpropylamine in place of cyclohexylamine, theabove-described compound was synthesized in accordance with the methoddescribed in Example 22(b).

Orange crystals

m.p.: 175°-177° C.

IR (KBr): 3600-3000, 2950, 2150, 1600 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.84 (9H, s), 1.01 (3H, d, J=6.0 Hz), 3.6-3.9(1H, m), 5.96 (2H, s), 6.10 (1H, d, J=10.0 Hz), 6.43 (1H, d, J=8.0 Hz),7.19 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.73 (1H, d, J=2.0 Hz), 8.55 (1H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 15.4, 26.1, 34.7, 55.0, 107.8, 117.2, 122.6,135.4, 145.0, 158.0, 158.6

EXAMPLE 26 (a) 3-Nitro-6-pyridylcarbonitrile

3-Nitro-6-bromopyridine (5.62 g, 27.7 mmol) and CuCN (3.32 g, 35.7 mmol)were mixed with 6 ml of DMF, followed by reaction at 100°-110° C. for 2hours. After cooling to room temperature, methylene chloride was addedto the reaction mixture. Then, the mixture was stirred, followed byrecovery of methylene chloride. After filtration using Celite, thefiltrate was concentrated and purified by silica gel columnchromatography (eluent: hexane:ethyl acetate=1:3 (v/v)) to obtain 2.74 gof a yellow solid (yield: 66%).

(b) 3-Amino-6-pyridylcarbonitrile

The nitropyridine compound (1.01 g) obtained in (a) described above wasdissolved in 10 ml of dioxane, and 0.5 g of 10% palladium-carbon wasadded thereto. Then, the solution was vigorously stirred in anatmosphere of hydrogen at room temperature. Palladium-carbon was removedby filtration using Celite and the filtered cake was washed withethanol. The filtrate and washings were combined and then concentrated.The residue was purified by silica gel column chromatography (eluent:hexane:ethyl acetate=1:3 (v/v)) to obtain 0.71 g of a light brown solid(yield: 88%).

(c) 3-Isothiocyanate-6-pyridylcarbonitrile

The aminopyridine compound (0.22 g, 1.85 mmol) obtained in (b) describedabove was suspended in 10 ml of toluene, and thiophosgene (0.16 ml, 2.1mmol) was added thereto, followed by reflux for 1 hour. Toluene wasremoved by distillation, and the residue was extracted with methylenechloride. The extracted fractions was purified by silica gel columnchromatography (eluent: hexane:ethyl acetate=4:1 (v/v)) to obtain 80 mgof an isothiocyanate as a yellow viscous liquid (yield: 27%).

(d) N-(6-cyano-3-pyridyl)-N'-(1,2,2-trimethylpropyl)-thiourea

The isothiocyanate compound (80 mg, 0.5 mmol) obtained in (c) describedabove was dissolved in 1 ml of methylene chloride, and1,2,2-trimethylpropylamine (0.15 ml, 1.12 mmol) was added thereto,followed by reaction at room temperature for several minutes. Then, thereaction mixture was purified by silica gel column chromatography(eluent: hexane:ethyl acetate=1:1 (v/v)) to obtain 0.13 g of a whitesolid (yield: 99%).

m p.: 146.0°-148.0° C.

IR (KBr): 3250, 3100, 2950, 2200, 1520 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.97 (1H, s), 8.79 (1H, d, J=2.4 Hz), 8.56 (1H,dd, J=8.6 Hz, 2.5 Hz), 7.99 (1H, d, J=9.2 Hz), 7.90 (1H, d, J=8.8 Hz),4.40-4.20 (1H, m), 1.08 (3H, d, J=6.7 Hz), 0.93 (9H, s)

EXAMPLE 27 (a) 3-Amino-6-pyridinecarboxyamide

3-Amino-6-pyridinecarbonitrile (0.45 g) was mixed with 5 ml ofmethanol-3 N sodium hydroxide-35% aqueous hydrogen peroxide (2:3:1(v/v)). After stirring at room temperature for 30 minutes, 5 ml of waterwas added to precipitate a solid. The precipitated solid was collectedby filtration, and washed with water and acetone, followed by drying.Thus, 0.29 g of a white powder was obtained (yield: 56%).

(b) N-(6-carbamoyl-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea.

The carboxyamide compound (0.37 g, 27 mmol) obtained in (a) describedabove and 1,2,2-trimethylpropyl isothiocyanate (1.15 g, 8.03 mmol) wereadded to 2 ml of DMF, followed by reaction at 80°-90° C. for about 40hours. DMF was removed by distillation, and the residue was purified bysilica gel column chromatography (eluent: chloroform: methanol=13:1(v/v)). Recrystallization from methanol-ether gave 0.4 g of the intendedproduct (yield: 53%).

White solid

m.p.: 197°-199° C.

IR (KBr): 3200, 2900, 1690, 1530 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.77 (1H, s), 8.74 (1H, d, J=2.3 Hz), 8.32 (1H,dd, J=8.4 Hz, 2.1 Hz), 7.97 (2H, d+s, J=8.4 Hz), 7.82 (1H, d, J=9.2 Hz),7.51 (1H, s), 4.45-4.25 (1H, m), 1.08 (3H, d, J=6.7 Hz), 0.94 (9H, s)

EXAMPLE 28 (a) 3-Nitro-6-methylaminopyridine

3-Nitro-6-chloropyridine (5 g, 31.5 mmol) was added to 10 ml of a 30%solution of methylamine in ethanol, followed by reaction at roomtemperature for 5 minutes. Then, recrystallization fromchloroform-hexane gave 4.92 g of the intended product as yellow crudecrystals.

(b) 3-Amino-6-methylaminopyridine

To 40 ml of an ethanol solution of the methylamino compound (4 g)obtained in (a) described above was added, 400 mg of platinum oxide,followed by reaction in an atmosphere of hydrogen at room temperaturefor 15 hours. The solvent was thereafter removed by distallation, andthe residue was purified by silica gel column chromatography (eluent:chloroform, and subsequently chloroform: methanol=20:1 (v/v)) to obtain320 mg of the intended product as brown crystals.

(c) N-(6-methylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea

523 mg (3.65 mmol) of 1,2,2-trimethylpropyl isothiocyanate was added to1.5 ml of a pyridine solution of the amino compound (300 mg, 2.44 mmol)obtained in (b) described above, and the mixture was stirred at roomtemperature for 18 hours. The precipitated crystals were collected byfiltration, and washed with hexane and ether, followed by drying. Thus,330 mg of the intended product was obtained (yield: 51%).

White crystals

m.p.: 195°-197° C.

IR (KBr): 3600-3000, 2950, 1620 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.85 (9H, s), 1.08 (3H, d, J=6.0 Hz), 2.96 (3H,d, J=5.0 Hz), 4.3-4.5 (1H, m), 4.9 (1H, brs), 5.58 (1H, d, J=6.0 Hz),6.44 (1H, d, J=9.0 Hz), 7.31 (1H, dd, J=2.0 Hz, 9.0 Hz), 7.43 (1H, brs),7.99 (1H, d, J=2.0 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 15.4, 26.3, 28.2, 34.4, 57.2, 106.8, 124.9,135.3, 144.1, 157.1, 181.7

Examples 29 TO 33

Using aniline (Example 29), ethylenediamine (Example 30),hydroxyethylamine (Example 31), imidazole (Example 32) and piperidine(Example 33) in place of methylamine, the following compounds weresynthesized in accordance with the method described in Example 28.

EXAMPLE 29N-(6-phenylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea

m.p.: 168°-170° C.

IR (KBr): 3500-3100, 3020, 2950, 1600, 1530 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.87 (9H, s), 1.09 (3H, d, J=6.0 Hz), 4.3-4.6(1H, m), 5.60 (1H, d, J=8.0 Hz), 6.91 (1H, d, J=8.0 Hz), 7.01 (1H, s),7.3-7.5 (6H, m), 7.65 (1H, s), 8.08 (1H, d, J=2.0 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 15.3, 26.3, 34.4, 57.2, 109.9, 117.6, 120.2,127.8, 128.6, 134.9, 141.8, 142.8, 152.9, 181.4

EXAMPLE 30N-[6-(2-aminoethyl)amino-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

m.p.: 138°-140° C.

IR (KBr): 3600-3000, 2950, 1615, 1530 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.85 (9H, s), 1.08 (3H, d, J=6.0 Hz), 2.97 (2H,t, J=6.0 Hz), 3.3-3.5 (2H, m), 4.3-4.6 (1H, m), 5.27 (1H, brs), 5.56(1H, d, J=8.0 Hz), 6.46 (1H, d, J=9.0 Hz), 7.28 (1H, dd, J=4.0 Hz, 9.0Hz), 7.52 (1H, brs), 7.97 (1H, d, J=4.0 Hz)

EXAMPLE 31N-[6-(2-hydroxyethylamino)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

IR (KBr): 3200, 3080, 3000, 2920, 1520, 1480, 1190 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.89 (7H, s), 1.03 (3H, d, J=6.6 Hz), 3.30 (2H,t, J=5.7 Hz), 3.53 (2H, t, J=5.7 Hz), 4.20-4.35 (1H, m), 4.60-4.75 (1H,br), 6.48 (1H, d, J=8.8 Hz), 6.48 (1H, s), 7.13 (1H, d, J=8.1 Hz), 7.38(1H, dd, J=8.8 Hz, 2.1 Hz), 7.81 (1H, d, J=2.1 Hz), 9.00 (1H, s)

EXAMPLE 32N-[6-(1-imidazolyl)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

IR (KBr): 3400-3200, 2900, 1610, 1180 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.93 (9H, s), 1.07 (3H, d, J=6.7 Hz), 4.25-4.40(1H, m), 7.11 (1H, s), 7.73-7.77 (1H, brs), 7.75 (1H, d, J=8.7 Hz), 7.90(1H, s), 8.28 (1H, dd, J=8.7 Hz, 2.5 Hz), 8.47 (1H, s), 8.50 (1H, d,J=2.5 Hz), 9.60 (1H, s)

EXAMPLE 33 N-(6-piperidino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea

m.p.: 151°-153° C.

IR (KBr): 3600-3000, 2900, 1600, 1535 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.86 (9H, s), 1.08 (3H, d, J=6.0 Hz), 1.66 (6H,brs), 3.57 (4H, brs), 4.3-4.6 (1H, m), 5.63 (1H, d, J=6.0 Hz), 6.67 (1H,d, J=8.0 Hz), 7.33 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.53 (1H, brs), 8.05 (1H,d, J=2.0 Hz)

EXAMPLE 34 (a) 2-Hydrazino-5-nitropyridine

2-Chloro-5-nitropyridine (5 g, 31.5 mmol) and hydrazine (1.74 g, 34.7mmol) were dissolved in 60 ml of dioxane, and the solution was stirredat room temperature for 16 hours. The precipitated yellow powder (m.p.:198°-208°0 C.) was collected by filtration to obtain 502 mg of theintended product as a hydrochloride salt.

(b) 6-(2-t-butoxycarbonylhydrazino)-3-nitropyridine

2-Hydrazino-5-nitropyridine hydrochloride (1 g, 5.3 mmol) was suspendedin the mixed solvent of 20 ml of dioxane, 1 ml of DMF and 2.5 ml oftriethylamine, and 2.4 ml of di-t-butyl dicarbonate was added theretowith stirring. The reaction solution was refluxed for 2 hours. Aftercompletion of the reaction, the reaction solution was filtered. Thesolvent was removed from the reaction solution by distillation underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent: hexane:ethyl acetate=3:2 (v/v)) to obtain 1.27 gof the intended product as a yellow powder (m.p.: 132.5°-134° C.).

(c) 3-Amino-6-(2-t-butoxycarbonylhydrazino)pyridine

57 mg of platinum oxide was added to a solution of6-(2-t-butoxycarbonylhydrazino)-3-nitropyridine (570 mg) in ethanol (10ml). The mixture was vigorously stirred in an atmosphere of hydrogen atroom temperature for 1 hour. After completion of the reaction, thereaction solution was filtered, and the filtered cake was thoroughlywashed with ethanol. The filtrate and the washings were combined, andthe solvent was removed by distillation to obtain 502 mg of3-amino-6-(2-t-butoxycarbonylhydrazino)pyridine as a brown powder.

(d)N-[6-(2-t-butoxycarbonylhydrazino)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

3-Amino-6-(2-t-butoxycarbonylhydrazino)pyridine (500 mg, 2.2 mmol) and1,2,2-trimethylpropyl isothiocyanate (351 mg, 2.5 mmol) were dissolvedin 10 ml of pyridine, and the solution was stirred at room temperaturefor 16 hours. After completion of the reaction, the solvent was removedby distillation under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent: hexane:ethyl acetate=1:3(v/v)) to obtain the powdery white intended product (m.p.: 143°-146°C.).

IR (KBr): 3250, 2950, 1690, 1530 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.90 (9H, s), 1.04 (3H, d, J=6 Hz), 1.42 (9H,s), 4.29 (1H, m), 6.48 (1H, d, J=8 Hz), 7.28 (1H, brd), 7.58 (1H, dd,J=2 Hz), 7.94 (1H, d, J=2.3 Hz), 8.07 (1H, s), 8.78 (1H, s), 9.08 (1H,s)

¹³ C-NMR (DMSO-d₆) δ ppm: 18.4 (q), 28.1 (q), 56.0 (q), 79.1 (d), 106.6(d), 124.7 (d), 133.0 (d), 137.6 (s), 152.3 (s), 156.2 (s), 187.9 (s)

EXAMPLE 35 N-(6-hydrazino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thioureahydrochloride

3.5 ml of 8.83 N solution of hydrochloric acid in ethanol was added to asolution of N-(6-t-butoxycarbonylhydrazino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea(150 mg, 0.41 mmol) obtained in Example 34 in ethanol (2 ml). Afterstirring at room temperature for 30 minutes, the solution was stirred inan ice bath for 30 minutes. Then, the solution was allowed to stand inan ice bath for 30 minutes, The precipitated blue powder was collectedby filtration, and dried to obtain 85 mg of the intended product.

IR (KBr): 3200, 1690, 1600, 1540 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.92 (9H, s), 1.04 (3H, d, J=6.7 Hz), 3.0-4.5(1H, br), 4.26 (1H, q, J=6.7 Hz), 6.85 (1H, d, J=9 Hz), 7.85 (1H, dd,J=2.1 Hz, 9.0 Hz), 8.07 (1H, d, J=8.6 Hz), 8.27 (1H, s), 9.1-9.5 (1H,s), 10.07 (1H, s)

EXAMPLE 36

Using t-butoxycarbonyl-glycine-N-hydroxysuccinimide ester in place ofdi-t-butyl dicarbonate, the following compounds were obtained by themethods described in Example 34.

(a)N-6-(2-t-butoxycarbonylqlycylhydrazino)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

IR (KBr) 3400, 1680 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.75 (1H, s), 9.09 (1H, s), 8.24 (1H, s), 7.95(1H, d, J=2.1 Hz), 7.57 (1H, dd, J=2.0 Hz, 8.7 Hz), 7.31 (1H, d, J=9.3Hz), 7.02 (1H, t), 6.57 (1H, d, J=8.8 Hz), 4.28 (1H, m), 3.62 (2H, d,J=5.9 Hz), 1.39 (9H, s), 1.04 (3H, d, J=6.6 Hz), 0.90 (9H, s)

(b)N-[6-(2-glycylhydrazino)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thioureahydrochloride

IR (KBr): 3400-3100, 1700 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 11.17 (1H, s), 10.74 (2H, s), 8.50 (1H, s),8.47-8.39 (4H, m), 8.13 (1H, dd, J=2.1 Hz, 9.4 Hz), 7.20 (1H, d, J=9.4Hz), 4.24 (1H, m), 3.86 (2H, d, J=5.3 Hz), 1.05 (3H, d, J=6.7 Hz), 0.93(9H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 180.71 (s), 166.78 (s), 150.16 (s), 141.16(d), 129.47 (d), 127.87 (s), 110.87 (d), 57.39 (d), 39.50 (t), 34.28(s), 26.34 (q), 15.18 (q)

EXAMPLE 37

Using 4-ethoxycarbonylpiperazine in place of di-t-butyl dicarbonate, thefollowing compounds were obtained by the methods described in Example34.

(a)N-6-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thiourea

IR (KBr): 3200, 1690 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 8.08 (1H, d, J=2.6 Hz), 7.43 (1H, bs), 7.38 (1H,dd, J=2.6 Hz, 9.0 Hz), 6.67 (1H, d, J=8.9 Hz), 5.59 (1H, d, J=9.8 Hz),4.40 (1H, m), 4.18 (2H, q, J=7.0 Hz), 3.60 (8H, s), 1.29 (3H, t, J=7.1Hz), 1.08 (3H, d, J=6.7 Hz), 0.86 (9H, s)

(b)N-6-(4-ethoxycarbonyl-1-piperazinyl)-3-pyridyl]-N'-(1,2,2-trimethylpropyl)thioureahydrochloride

IR (KBr): 3250, 1700 cm⁻¹ ¹ H-NMR (CDCl₃) δ ppm: 10.74 (1H, bs), 9.01(1H, d, J=9.0 Hz), 7.93 (1H, s), 7.83 (1H, d, J=9.1 Hz), 6.95 (1H, d,J=9.6 Hz), 4.35 (1H, m), 4.19 (2H, q, J=7.1 Hz), 3.75 (8H, m), 1.30 (3H,t, J=7.1 Hz), 1.17 (3H, d, J=6.7 Hz), 1.01 (9H, s)

¹³ C-NMR (CDCl₃) δ ppm: 181.24 (s), 155.04 (s), 149.04 (s), 143.45 (d),129.86 (s), 128.22 (d), 110.09 (d), 62.00 (t), 58.45 (d), 46.71 (t),42.54 (t), 34.55 (s), 26.47 (q), 15.29 (q), 14.54 (q)

EXAMPLE 38 (a) 2-Acetylamino-5-nitropyridine

To a solution of 2-amino-5-nitropyridine (4.0 g, 28.8 mmol) indichloromethane (15 ml) were added 176 mg (31.6 mmol) of4-N,N'-dimethylaminopyridine (DMAP), 4.41 ml of triethylamine (31.6mmol) and 2.16 ml (31.6 mmol) of acetyl chloride in turn, and themixture was stirred at room temperature for 1 hour. A 1 M aqueoussolution of potassium carbonate was added to the mixed suspension toneutralize it. Extraction with chloroform was repeated three times, andthe extract was dried over magnesium sulfate. The solvent was removed,and the residue was subjected to silica gel column chromatography(eluent: chloroform). Recrystallization from chloroform-hexane gave 2.14g of the intended product as a flesh-colored powder (yield: 49%).

(b) 2-Acetylamino-5-aminopyridine

100 mg of platinum oxide was suspended in a solution of2-acetylamino-5-nitropyridine (1.0 g, 5.52 mmol) in ethanol (20 ml). Thesuspension was stirred in an atmosphere of hydrogen at room temperaturefor 1.5 hours. Platinum oxide was removed by filtration using Celite,and the solvent was removed by distillation under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform alone to chloroform:methanol=10:1 (v/v)) to obtain 170 mg ofthe intended product as dark brown crude crystals (yield: 20%).

(c) N-(6-acetylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea

To a solution of 2-acetylamino-5-aminopyridine (150 mg, 0.99 mmol) inpyridine (1.5 ml), 213 mg (1.49 mmol) of 1,2,2-trimethylpropylisothiocyanate was added dropwise, followed by stirring at roomtemperature for 22 hours, at 50° C. for 5 hours and further at roomtemperature for 15 hours. Then, the solvent was removed by distillationunder reduced pressure. The residue was recrystallized fromchloroform-hexane to obtain 232 g of the intended product as aflesh-colored powder (yield: 79%).

m.p.: 197°-199° C.

IR (KRr): 3500-3000, 2950, 1670, 1590 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 0.92 (9H, s), 1.06 (3H, d, J=6.0 Hz), 2.08 (3H,s), 4.32 (1H, m), 7.53 (1H, d, J=8.0 Hz), 7.84 (1H, dd, J=1.0 Hz, 8.0Hz), 8.01 (1H, d, J=8.0 Hz), 8.35 (1H, d, J=1.0 Hz), 9.35 (1H, s), 10.42(1H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 15.2, 23.7, 26.3, 34.3, 57.2, 112.6, 132.1,133.2, 142.8, 148.2, 168.8, 181.0

EXAMPLE 39 N-(6-benzoylamino-3-pyridyl)-N'-1,2,2-trimethylpropylthiourea

Using benzoyl chloride in place of acetyl chloride, the above-describedcompound was synthesized in accordance with the method described inExample 38.

m.p.: 168°-170° C.

IR (KBr): 3600-3000, 2950, 1650, 1610 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.87 (9H, s), 1.01 (3H, d, J=6.0 Hz), 4.25 (1H,brs), 7.3-7.6 (4H, m), 7.8-8.2 (4H, m), 8.41 (1H, s), 9.36 (1H, s),10.68 (1H, s)

EXAMPLES 40 To 42

Using 2-methylpropyl isothiocyanate (Example 40), 1-dimethylpropylisothiocyanate (Example 41) and exo-2-norbornyl isothiocyanate (Example42) in place of 1,2,2-trimethylpropyl isothiocyanate, the followingcompounds were synthesized in accordance with the method described inExample 21.

EXAMPLE 40 N-(6-amino-3-pyridyl)-N'-(2-methylpropyl)thiourea

IR (KBr): 3300, 2950, 1550, 1350, 1280 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.88 (6H, d, J=6.7 Hz), 1.90 (1H, d, hept, J=6.9Hz, 6.7 Hz), 3.43 (2H, dd, J=6.9 Hz, 5.7 Hz), 4.70 (2H, brs), 5.73 (1H,brs), 6.55 (1H, dd, J=8.6 Hz, 0.6 Hz), 7.32 (1H, dd, J=8.6 Hz, 2.6 Hz),7.49 (1H, brs), 7.97 (1H, d, J=2.6 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 20.1 (q), 27.5 (d), 51.4 (t), 107.5 (d), 124.7(s), 135.7 (d), 144.8 (d), 157.6 (s), 181.8 (s)

EXAMPLE 41 N-(6-amino-3-pyridyl)-N'-(1,1-dimethylpropyl)thiourea

IR (KBr): 3180, 2950, 1630, 1530, 1250, 1190 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 0.82 (3H, t, J=7.5 Hz), 1.43 (6H, s), 1.90 (2H,q, J=7.5 Hz), 4.76 (2H, brs), 5.56 (1H, brs), 6.54 (1H, dd, J=8.7 Hz,0.4 Hz), 7.31 (1H, dd, J=8.7 Hz, 2.6 Hz), 7.51 (1H, brs), 7.92 (1H, d,J=2.6 Hz)

¹³ C-NMR (DMSO-d₆) δ ppm: 8.2 (q), 26.5 (q), 32.0 (d), 55.2 (s), 107.3(d), 125.1 (s), 135.9 (d), 144.4 (d), 157.3 (s), 180.9 (s)

EXAMPLE 42 N-(6-amino-3-pyridyl)-N'-(exo-2-norbornyl)thiourea

IR (KBr): 3350, 2950, 1630, 1520, 1400, 1280 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm:

1.00-1.75 (8H, m), 2.15-2.30 (2H, m), 3.70-4.05 (1H, m), 5.82 (2H, brs),6.39 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=8.8 Hz, 2.5 Hz), 7.40 (1H, brs),7.74 (1H, d, J=2.5 Hz), 8.77 (1H, brs)

¹³ C-NMR (DMSO-d₆) δ ppm: 26.0 (t), 27.9 (t), 35.1 (t), 38.9 (t), 35.2(d), 41.7 (d), 56.8 (d), 107.1 (d), 125.4 (s), 135.5 (d), 144.5 (d),157.3 (s), 180.9 (s)

EXAMPLE 43 (a) N-(6-amino-3-pyridyl)-N'-(exo-2-norbornyl)carbodiimide

To a solution of the thiourea compound (2 g, 7.62 mmol) of Example 42 inmethylene chloride-ethanol (1:1 (v/v), 100 ml) were added 4.95 g (27.9mmol) of mercuric oxide and 0.122 g (3.81 mmol) of sulfur, and themixture was stirred at room temperature for 3 days. Mercuric oxide,mercuric sulfide and sulfur were filtered off using Celite, and thefiltered cake was washed with methylene chloride. The filtrate and thewashings were combined, and the solvent was removed by distillation toobtain 1.77 g of the intended product.

(b) N-(6-amino-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)-guanidine

To 20 ml of a methylene chloride solution of the carbodiimide compound(1.743 g, 7.63 mmol) obtained in (a) described above, 0.641 g (15.27mmol) of cyanamide and a drop of N,N-diisopropylethylamine were added,and the mixture was stirred at room temperature for one day. The solventwas removed by distillation, and the residue was purified by silica gelcolumn chromatography (eluent: chloroform:methanol=10:1 (v/v)), followedby recrystallization from methylene chloride-methanol-ether. Thus, 1.538g of the intended product was obtained.

White powder

m.p.: 180°-181° C.

IR (KBr): 3300, 2900, 2150, 1585, 1490, 1375 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 1.00-1.70 (8H, m), 2.10-2.25 (2H, m), 3.50-3.65(1H, m), 5.92 (2H, brs), 6.41 (1H, d, J=8.6 Hz), 6.45 (1H, d, J=5.9 Hz),7.18 (1H, dd, J=8.6 Hz, 2.6 Hz), 7.70 (1H, d, J=2.6 Hz), 8.44 (1H, brs)

EXAMPLE 44 (a)N-[6-3-(3-benzyloxycarbonyl-5-oxo-4-oxazolidinyl)propionylamino]-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine

To 922 mg of N-(6-amino-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)guanidine obtained in Example 43 were simultaneously added dropwise asolution (: ml) of 3-(S)-(3-benzyloxycarbonylbornyl-5-oxo-4-oxazolidinyl)propionyl-chloride(1.06 g, 3.41 mmol) in DMF and a solution (1 ml) of triethylamine (0.475ml) in DMF. After completion of the dropping, the mixture was stirred atroom temperature for 16 hours. After completing the reaction, thesolvent was removed from the reaction mixture by distillation underreduced pressure, and then the residue was purified by silica gelchromatography [eluent: methanol:chloroform=1:20 (v/v)] to obtain 394 mgof the intended product (yield: 21.2%).

(b)N-[6-(benzyloxycarbonyl-γ-L-glutamylamino)-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine

[6-[3-(3-benzyloxycarbonyl-5-oxo-4-oxazolidinyl)-propionylamino]-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine (410 mg, 0.76 mmol) was dissolved in 15 ml of THF and 0.75 mlof 1N sodium hydroxide was added thereto with stirring at roomtemperature. The mixture was stirred at room temperature for 20 minutes,followed by removal of the solvent by distillation under reducedpressure. The residue was purified by silica gel chromatography [eluent:methanol:chloroform=1:2 (v/v)]to obtain 370 mg of the intended product(yield: 92.3%).

N-[6-(γ-L-glutamylamino)-3-pyridyl-N"-cyano-N'-(exo-2-norbornyl)guanidine

N-[6-(benzyloxycarbonyl-γ-L-glutamylamino)-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine (20 mg, 0.0375 mmol) and 4 mg of lithium hydroxide were addedto 1 ml of water. After atmosphere was completely replaced withnitrogen, palladium-carbon was added to the mixture. Then the atmospherewas replaced with hydrogen and the mixture was vigorously stirred in anatmosphere of hydrogen at room temperature for 2 hours. After completionof the reaction, the reaction mixture was filtered and the filtratedcake was thoroughly washed with water. The filtrate and the washingswere combined, and the solution was neutralized with 1N-hydrochloricacid, followed by removal of the solvent by distillation. The residuewas purified by HPLC to obtain 6 mg of the intended product as a whitepowder (yield: 40%).

m.p. 200°-204° C. IR (KBr): 3200, 2950, 2200, 1680 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 10.7 (1H, br), 8.15 (1H, d, J=2.6 Hz), 7.99(1H, d, J=8.9 Hz), 7.79 (1H, br), 7.60 (1H, dd, J=2.6, 8.9 Hz), 3.70(1H, br), 3.27 (1H, t, J=6.3 Hz), 2.50 (2H, br), 2.21 (2H, br), 1.91(2H, q, J=6.3 Hz), 1.00-1.80 (8H, m)

EXAMPLES 45 To 50

Using N-(6-amino-3-pyridyl)-N"-cyano-N'(exo-2-norbornyl)guanidine as astarting material, the compounds of Examples 45 to 49 were obtainedusing the following reagents by the following methods:

    ______________________________________                                        Example                                                                       No.     Reagent           Method                                              ______________________________________                                        45      benzyloxycarbonyl alanine                                                                       DDC condensation                                    46      ethyl chloroformate                                                                             see Example 38                                      47      benzyl chloroformate                                                                            see Example 38                                      48      n-hexyl isocyanate                                                                              see Example 38                                      49      6-(5-methyl-2-oxo-2H-1,3-                                                                       standard                                                    dioxole-4-yl)methyl chloride                                                                    N-alkylation                                        ______________________________________                                    

The compounds of Example 50 was obtained in accordance with the methodin Example 28 by using 2-oxopropylamine ethylene ketal andexo-2-norbornyl isothiocyanate in place of methylamine and1,2,2-trimethylpropyl isothiocyanate respectively. Hydrochlorides ofExample 46 and 47 were obtained by a conventional method such as Example14(c) and (d).

EXAMPLE 45 N-(6-L-alanylamino-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)guanidine White Powder

m.p. 154.0°-158° C.

¹ H-NMR (DMSO-d₆) δ ppm: 8.15 (1H, d, J=2.7 Hz), 8.07 (1H, d, J=8.9 Hz),7.62 (1H, dd, J=8.9, 2.7 Hz), 7.02 (1H, d, J=6.5 Hz), 3.55-3.75 (1H, m),3.51 (1H, q, J=6.8 Hz), 3.0-3.9 (2H, br), 2.15-2.30 (2H, m), 1.23 (3H,d, J=6.8 Hz), 1.00-1.80 (8H, m)

EXAMPLE 46N-(6-ethoxycarbonylamino-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)guanidine hydrochloride White Powder

m.p. 144°-145° C.

IR (KBr): 3200, 2950, 2200, 1740 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 10.50 (1H, s), 9.16 (1H, s), 8.17 (1H, d, J=1.4Hz), 7.74 (2H, m), 7.18 (1H, d, J=6.6 Hz), 4.18 (2H, q, J=7.1 Hz), 3.68(1H, m), 2.24 (2H, m), 1.72-1.07 (8H, m), 1.26 (3H, t, J=7.1 Hz)

EXAMPLE 47N-(6-benzyloxycarbonylamino-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)quanidine hydrochloride White Powder

m.p. 152°-153° C.

IR (KBr): 3200, 2950, 2200, 1720 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 10.76 (1H, s), 9.29 (1H, s), 8.21 (1H, d, J=2.5Hz), 7.82-7.71 (2H, m), 7.43 (5H, m), 7.27 (1H, d, J=6.7 Hz), 5.21 (2H,s), 3.70 (1H, m), 2.23 (2H, m), 1.72-1.08 (8H, m)

EXAMPLE 48 N-[6-(hexylureido)-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl)guanidine Colorless Needle-like Crystal

m.p. 157°-158° C.

IR (KBr): 3400-3100, 2950, 2850, 2118, 1670, 1498 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.16 (1H, s), 8.73 (1H, s), 8.04 (1H, br), 8.00(1H, d, J=2.5 Hz), 7.49 (1H, dd, J=2.5 Hz, 8.9 Hz), 7.33 (1H, d, J=8.9Hz), 6.75 (1H, d, J=6.6 Hz), 3.61 (1H, brs), 3.17 (2H, q, J=6 3 Hz),2.22 (2H, br), 1.55-1.70 (1H, m), 1.00-1.55 (15H, m), 0.88 (3H, t, J=6.3Hz)

EXAMPLE 49 (a)N-[6-(5-methyl-2-oxo-2H-1,3-dioxole-4-ylmethylamino)-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine

IR (KBr): 3250, 2900, 2200, 1800, 1720 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.50 (1H, s), 7.83 (1H, d, J=2.3 Hz), 7.25 (1H,dd, J=2.4, 8.7 Hz), 7.04 (1H, t, J=5.7 Hz), 6.51 (1H, d, J=8.7 Hz), 6.52(1H, s), 4.29 (2H, d, J=5.6 Hz), 3.56 (1H, m), 2.19 (2H, m), 2.15 (3H,s), 1.66-1.04 (8H, m)

(b) N-[6-(5-methyl-2-oxo-2H-1,3-dioxole-4-ylmethylamino)-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl) quanidine hydrochloride Light Yellow Powder

m p. 151°-152° C. IR (KBr): 3200, 2900, 2150, 1800, 1730 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 9.07 (1H, s), 8.60 (1H, s), 7.94 (1H, d, J=2.2Hz), 7.78 (1H, dd, J=2.0, 9.3 Hz), 7.12 (1H, d, J=6.5 Hz), 7.00 (1H, d,J=9.3 Hz), 4.53 (2H, s), 3.65 (1H, m), 2.23 (2H, m), 2.19 (3H, s),1.71-1.06 (8H, m)

EXAMPLE 50 6-(2-oxopropylamino)-3-pyridyl]-N"-cyano-N'-(exo-2-norbornyl)guanidine Light Yellow Powder

m.p. 117°-119° C.

IR (KBr): 3500, 3350, 3200, 3000, 2950, 2150, 1720, 1590, 1610 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 7.94 (1H, d, J=2.0 Hz), 7.25 (1H, dd, J=2.0, 10.0Hz), 7.16 (1H, brs), 6.54 (1H, d, J=10.0 Hz), 5.50 (1H, t, J=7.0 Hz),4.46 (1H, d, J=3.0 Hz), 4.29 (2H, d, J=7.0 Hz), 3.55-3.7 (1H, m), 2.27(3H, s), 2.15-2.25 (2H, m), 1.0-1.9 (8H, m)

EXAMPLE 51 (a)N-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimid

N-(6-amino-3-pyridyl)-N'-1,2,2-trimethylpropylthiourea (1.26 g, 5.29mmol) obtained in Example 21 was dissolved in 10 ml of THF in anatmosphere of nitrogen and 7.38 ml of triethylamine andmethanesulfonylchloride (0.41 ml, 5.29 mmol) were successively addeddropwise thereto under ice cooling. After completion of the dropping,the mixture was stirred at room temperature for 1.5 hour, followed byaddition of water. Extraction with chloroform was repeated three times,the extract was dried and the solvent was removed by distillation. Theresidue was purified by silica gel column chromatography [eluent:chloroform:methanol =100:1 to 10:1 (v/v)] and subjected torecrystallization from chloroform-ether to obtain 210 mg of the intendedproduct (yield: 13%).

White Crystal

IR (KBr): 3600-3100, 3000, 2950, 2850, 2100 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.04 (1H, d, J=2.0 Hz), 7.47 (1H, dd, J=2.0,8.0 Hz), 6.95 (1H, d, J=8.0 Hz), 3.54 (1H, q, J=6.0 Hz), 3.27 (3H, s),1.25 (3H, d, J=6.0 Hz), 0.92 (9H, s)

¹³ C-NMR (DMSO-d₆) δ ppm: 154.8, 145.8, 137.2, 133.0, 128.3, 113.1,52.6, 41.5, 34.1, 26.1, 16.4

(b)N-(6-methanesulfonylamino-3-pyridyl)-N"-cyano-N'-(1,2,2-trimethylpropyl)guanidine

Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1mmol) were added to 1 ml of a solution ofN-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide(121 mg, 0.41 mmol) in chloroform and the mixture was stirred at roomtemperature for 16 hours. After an insoluble matter was removed byfiltration, the filtrate was concentrated. The residue was purified bysilica gel column chromatography [eluent: chloroform alone tochloroform:methanol =5:1 (v/v)] and subjected to recrystallization fromchloroform-ether to obtain 97 mg of the intended product (yield: 72%).

White Crystal

m.p. 164°-166° C.

IR (KBr): 3600-3000, 2990, 2290, 2200 cm⁻¹

¹ H-NMR (DMSO-d₆) δ ppm: 8.94 (1H, s), 8.11 (1H, d, J=2.0 Hz), 7.58 (1H,dd, J=2.0, 7.0 Hz), 6.95 (1H, d, J=7.0 Hz), 6.73 (1H, d, J=8.0 Hz),3.7-3.95 (1H, m), 3.27 (3H, s), 1.06 (3H, d, J=6.0 Hz), 0.88 (9H, s)

EXAMPLE 52 N-(6-methylthio-3-pyridyl)-N'-(1,2,2-trimethylpropyl)thiourea

Using methanethiol in place of methylamine, the above-described compoundwas synthesized in accordance with the method described in Example 28.

White Powder

m.p. 157.0°-158.0° C.

IR (KBr): 3220, 2950, 1530, 1465, 1140 cm⁻¹

¹ H-NMR (CDCl₃) δ ppm: 8.36 (1H, d, J=2.5 Hz), 7.83 (1H, brs), 7.41 (1H,dd, J=8.7, 2.5 Hz), 7.25 (1H, dd, J=8.7, 0.5 Hz), 5.60-5.85 (1H, brd),4.25-4.55 (1H, m), 2.58 (3H, s), 1.11 (3H, d, J=6.7 Hz), 0.89 (9H, s)

EXAMPLES 53 To 83

The compounds shown in Table 4 were synthesized in accordance with themethods described in Examples 1-8 or 21. The properties of the obtainedcompounds were shown in Table 4 in which the symbol "*" at the column ofthe compound (R) indicates the binding position.

                                      TABLE 4                                     __________________________________________________________________________     ##STR10##                                                                                                  Specific                                                                      rotation [α].sub.D                        Example                                                                            Compound                 (temperature,                                   No.  (R)        m.p. (°C.)                                                                   Appearance                                                                            solvent)                                        __________________________________________________________________________    (A) ZS                                                                        53                                                                                  ##STR11## 178-180                                                                             red brown crystal                                                                     [α].sub.D.sup.20 = +16.7 (c 0.2,                                        MeOH)                                           54                                                                                  ##STR12## 174-180                                                                             light pink crystal                                      55 (Hydro- chloride)                                                                ##STR13## unmeasur- able                                                                      light brown amorphous                                   56                                                                                  ##STR14## 174-175.5                                                                           light pink crystal                                      57                                                                                  ##STR15## 173-174                                                                             light pink crystal                                      58                                                                                  ##STR16## 138-140                                                                             white crystal                                           59                                                                                  ##STR17## 165-167                                                                             light needle- like crystal                              60                                                                                  ##STR18## 112-114                                                                             gray crystal                                                                          [α].sub.D.sup.22 = +15.5 (c 0.2,                                        MeOH)                                           61                                                                                  ##STR19## 152-154.5                                                                           light brown crystal                                     62                                                                                  ##STR20## 153-154                                                                             colorless transparent prism crystal                     63                                                                                  ##STR21## 188-189                                                                             red brown crystal                                       64                                                                                  ##STR22## 178-180                                                                             brown crystal                                                                         [α].sub.D.sup.22 = -2.7 (c 0.3,                                         MeOH)                                           65 (Hydro- chloride)                                                                ##STR23## 190 (Decom- position)                                                               brown crystal                                                                         [α].sub.D.sup.22 = +7.0 (c 0.2,                                         MeOH)                                           66 (Hydro- chloride)                                                                ##STR24## 153-154                                                                             light brown powder                                      67                                                                                  ##STR25## 182-184                                                                             red brown crystal                                       68 (Hydro- chloride)                                                                ##STR26## 206-207                                                                             dark brown crystal                                      69                                                                                  ##STR27## 187-188                                                                             gray brown crystal                                      70                                                                                  ##STR28## 171-172                                                                             pink needle-like crystal                                71                                                                                  ##STR29## 142-143                                                                             light brown plate-like crystal                          72                                                                                  ##STR30## 168-169                                                                             colorless plate-like crystal                            73                                                                                  ##STR31## 90-92  violet amorphous                                       74                                                                                  ##STR32## 109-110                                                                             violet amorphous                                        75                                                                                  ##STR33## 166-168                                                                             mauve crystal                                           76 (cys form)                                                                       ##STR34## 176-177.5                                                                           brown needle- like crystal                              77 (trans form)                                                                     ##STR35## 194-196                                                                             white powder                                            (B) ZNCN                                                                      78                                                                                  ##STR36## 183-190                                                                             white needle- like crystal                              79                                                                                  ##STR37## 189-190                                                                             colorless needle-like crystal                           80                                                                                  ##STR38## 208.5-210                                                                           white needle- like crystal                              81 (Hydro- chloride)                                                                ##STR39## 220-225 (Decom- position)                                                           white powder                                            82   C(CH.sub.3).sub.3                                                                        220-221                                                                             light red                                                                     crystal                                                 83   C(CH.sub.3).sub.3                                                                        213-217                                                                             white crystal                                           (Hydro-                                                                       chloride)                                                                     __________________________________________________________________________

EXAMPLE 84N-(6-aminopyridine-1-oxido-3-yl)-N"-cyano-N'-(1,2,2-trimethylpropyl)guanidine

N-(6-amino-3-pyridyl)-N"-cyano-N'-(1,2,2-trimethylpropyl) guanidine(1.757 g, 6.749 mmol) obtained in Example 25 was dissolved in a mixedsolvent of methylene chloride-methanol (4:1 (v/v), 25 ml),m-chloroperbenzoic acid (1.664 g, purity: 70%, 6.749 mmol) was graduallyadded thereto under ice cooling. The reaction mixture was stirred underice cooling for 2 hours and 50 mg of sodium sulfite was added theretofollowed by stirring for 10 minutes. Then, 30 ml of a 10% potassiumcarbonate aqueous solution was added to the reaction mixture andsubjected to extraction with chloroform. After the extract was dried,the solvent was removed. The residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=10:1 (v/v)).Recrystallization from methanol-methylene chloride-ether gave 1.459 g ofthe intended product (yield 78.2%).

Light Brown Powder

m.p. 141.0°-146.0° C.

¹ H-NMR (DMSO-d₆) δ ppm: 8.78 (1H, s), 7.90 (1H, d, J=2.2 Hz), 6.98 (1H,dd, J=8.8, 2.2 Hz), 6.77 (2H, s), 6.77 (1H, d, J=8.8 Hz), 6.61 (1H, d,J=9.2 Hz), 3.65-3.90 (1H, m), 1.01 (3H, d, J=6.8 Hz), 0.85 (9H, s)

EXAMPLE 85

Using N-(6-amino-3-pyridyl)-N"-cyano-N'-(exo-2-norbornyl) guanidineobtained in Example 43 as a starting material, the following compoundwas obtained in the same manner as Example 84.

N-(6-aminooyridine-1-oxido-3-yl)-N"-cyano-N'-(exo-2-norbornyl)guanidineWhite Powder

m.p. 156.0°-160.0° C.

¹ H-NMR (DMSO-d₆) δ ppm: 8.66 (1H, s), 7.90 (1H, d, J=2.2 Hz), 6.98 (1H,dd, J=8.9, 2.2 Hz), 6.75 (1H, brs), 6.75 (1H, d, J=8.9 Hz), 6.75 (2H,s), 3.45-3.65 (1H, m), 2.10-2.25 (2H, m), 1.00-1.70 (8H, m)

EXAMPLES 86 To 88

The compounds shown in Table 5 were synthesized in accordance with themethod described in Example 84.

                  TABLE 5                                                         ______________________________________                                         ##STR40##                                                                    Ex-                                                                           ample                                                                         No.   Compound (R)                                                                              m.p. (°C.)                                                                          Appearance                                     ______________________________________                                        86                                                                                   ##STR41##  231-232 (Decomposition)                                                                    milk-white powder                              87                                                                                   ##STR42##  155-161 (Decomposition)                                                                    light yellow linear crystal                    88    C(CH.sub.3).sub.3                                                                         231-232      white powder                                   ______________________________________                                    

EXAMPLES 89 To 92

The compounds shown in Table 6 were synthesized in accordance with themethod described in Example 45.

                  TABLE 6                                                         ______________________________________                                         ##STR43##                                                                    Ex-                                                                           ample                                                                         No.   Compound (R)  m.p. (°C.)                                                                          Property                                     ______________________________________                                        89    NH.sub.2 CH.sub.2                                                                           210-211      colorless plate-                                                 (Decomposition)                                                                            like crystal                                 90                                                                                   ##STR44##    123-126                                                   91                                                                                   ##STR45##    114-116                                                   92                                                                                   ##STR46##    unmeasur- able (Hygroscopic)                                                               light yellow solid                           ______________________________________                                    

EXAMPLE 93 6-Amino-3-(2-endo-norbornylamino-2-nitroethenylamino)pyridine

The above-described compound can be synthesized in accordance with themethod described in Example 23 except for using 2,5-diaminopyridine inplace of 3,4-diaminopyridine.

PHARMACOLOGICAL TESTS

In order to show the utility of the compounds of the present invention,results of pharmacological tests for typical compounds are shown below.

(A) Vasodepressor Activity (1) Test method

Male Wistar rats having a body weight of 300 g were used for the test.The rat intravenously anesthetized with 50 mg/kg of pentobarbital sodiumwas fixed at its back, and a polyethylene catheter was inserted into theleft common carotid artery for measurement of the blood pressure. Theblood pressure and the heart rate were continuously recorded on apolygraph through a tachometer and a pressure transducer. The drug wasgiven in bolus form through a wing-like needle placed in the caudalvein.

(2) Test results

Test results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                          Maximum Effect (%)                                          Test Compound                                                                             Dosage      Diastolic                                                                              Systolic                                     (Example No.)                                                                             (mg/kg)     Pressure Pressure                                     ______________________________________                                         7          3           73       59                                           24          3           71       52                                           ______________________________________                                         note: Maximum effect indicates the parcentage of the lowest blood pressur     after administration of the drug based on the blood pressure before the       administration of the drug.                                              

(B) Activity on Autonomous Contraction of Portal Vein Extirpated fromRat (1) Test method

A male Wistar rat having a body weight of 300 g was slaughtered bystriking a blow at the occipital region, and the portal vein wasextirpated therefrom. The extirpated vein was cut longitudinally toprepare strip section samples about 1 cm in length. The portal veinsamples to which a load of 0.5 g was applied were suspended in Lockesolution aerated with a mixed gas (95% O₂ and 5% CO₂) in a Magnus bathat 37° C., and changes in contraction tension were recorded on a thermalstylus recorder through a transducer.

The portal vein samples were thus allowed to conduct a rhythmic movementfor about 30 minutes. When the rhythm was stabilized, the drug wasaccumulatively added. To the samples in which the automatic rhythm ofthe portal vein disappeared by addition of the drug, glibenclamide as apotassium channel blocker, was added at a concentration of 10⁻⁶ to 10⁻⁵M, or 3,4-diaminopyridine at a concentration of 10⁻⁴ to 10⁻³ M, wherebythe recovery of the automatic rhythm was examined.

(2) Test results

Test results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Test Compound                                                                 (Example No.)   IC.sub.100 (μM)                                            ______________________________________                                         7              10                                                            24               1                                                            ______________________________________                                    

For the test compounds, the autonomous contraction of the rat portalvein was allowed to disappear at the IC₁₀₀ concentrations shown in Table3. The autonomous contraction was recovered by adding glibenclamide at10⁻⁶ M or 3,4-diaminopyridine at 10⁻³ M.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. An aminopyridine compound represented by theformula: ##STR47## wherein n represents 0 to 1; Z represents ═S, ═NCN or═CHNO₂ ; R₁ represents --NR₃ R₄, --NHNR₃ R₄, --NHCONHR₃ or --NHSO₂ R₃ ;R₂ represents H, substituted or unsubstituted alkyl, or substituted orunsubstituted cycloalkyl; R₃ and R₄, which may be the same or different,represent H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted alphatic acyl or aromatic acyl, or alkoxycarbonylgroup; and R₃ and R₄ may form a substituted or unsubstitutedheterocyclic ring together with the nitrogen atom to which R₃ and R₄ arebound, which ring may include another heteroatom and may containunsaturation;wherein each alkyl group has from 1 to 10 carbon atoms,each cycloalkyl group has from 5 to 10 carbon atoms, the aryl isselected from the group consisting of phenyl and naphthyl, the aliphaticacyl is selected from the group consisting of acetyl, propionyl,butyryl, isobutyryl, valeryl, and pivaloyl, the aromatic acyl isselected from the group consisting of benzoyl, naphthoyl and toluoyl,and the alkoxycarbonyl has an alkoxy portion having from 1 to 7 carbonatoms, wherein each substituted alkyl contains a substituent selectedfrom the group consisting of hydroxyl and amino, each substitutedcycloalkyl contains an alkyl substituent, the substituted aryl containsa substituent selected from the group consisting of alkyl, halogen,nitro, and cyano, and the substituted acyl contains a substituentselected from the group consisting of amino, lower alkoxycarbonylamino,carboxy, and a heterocyclic ring, wherein each heterocyclic ring isselected from the group consisting of pyrrolidinyl, piperidino,pyrrolinyl, pyrrolyl, piperazinyl, morpholino, thiomorpholino,imidazolinyl, imidizolidinyl, imidazolyl and pyrazolidinyl, wherein thesubstituted heterocyclic ring contains a substituent selected from thegroup consisting of alkyl, acyl, aryl and alkoxycarbonyl as definedabove; or a pharmaceutically acceptable acid salt thereof.
 2. Thecompound of claim 1, wherein each alkyl group is straight or branchedchain.
 3. The compound of claim 2, wherein each alkyl group is straightor branched chain containing 1 to 10 carbon atoms.
 4. The compound ofclaim 1, wherein each cyclo alkyl group is a monocycloallyl groupcontaining 5 to 7 carbon atoms.
 5. The compound of claim 1, wherein eachcyclo alkyl group is a bicycloalkyl group containing 7 to 10 carbonatoms.
 6. The compound of claim 1, wherein the acyl group is analiphatic acyl group.
 7. The compound of claim 1, wherein the acyl groupis an aromatic acyl group.
 8. The compound of claim 1, wherein thealkoxy component in the alkoxycarbonyl group has from 1 to 4 carbonatoms.
 9. The compound of claim 1, wherein when R₃ and R₄ combine withthe nitrogen to form a heterocyclic ring, R₃ and R₄ are independentlyalkylene or alkenylene, wherein the alkylene is selected from the groupconsisting of methylene, ethylene, trimethylene, propylene,tetramethylene, and 1,2-dimethylethylene, and the alkenylene is selectedfrom the group consisting of 1-butenylene and 1,3-butadienylene.
 10. Thecompound of claim 8, wherein the heterocyclic ring formed is imidazolylof ##STR48## in which R₅ is H, alkyl, acyl, aryl or alkoxycarbonyl. 11.The compound of claim 1, wherein R₁ is bound at the 4-position of thepyridine ring.
 12. The compound of claim 1, wherein R₁ is bound at the6-position of the pyridine ring.
 13. The compound of claim 1, whereinthe group --NH--C(═Z)--NHR₂ is bound at the 3-position of the pyridinering.
 14. The compound of claim 1, wherein Z is ═S.
 15. The compound ofclaim 1, wherein Z is ═NCN.
 16. The compound of claim 1, wherein Z is--CHNO₂.
 17. A process for treating hypertension which comprisesadministering to a patient in need of treatment for hypertension, ahypertension reducing effective amount of a compound of claim
 1. 18. Aprocess for treating ischemic heart disease which comprisesadministering to a patient in need of treatment for ischemic heartdisease an ischemic heart disease treating effective amount of acompound of claim
 1. 19. A process for vasodilating the peripheral,coronary or cerebral blood vessels which comprises administering, to apatient in need of vasodilation, an amount of a compound of claim 1effective to dilate the peripheral, coronary or cerbral blood vessels.20. A process for treating lipodysbolism which comprises administeringto a patient in need of treatment for lipodysbolism, a lipodysbolismtreating effective amount of a compound of claim 1.